Oxepanes and processes therefor

ABSTRACT

Chemical compounds having a substituted oxepane ring and methods of preparing such compounds are described. The compounds are active as utero-evacuant agents.

This is a continuation of application Ser. No. 29,231, filed Apr. 11,1979, now abandoned, which in turn is a divisional of Ser. No. 903,456filed May 8, 1978, now U.S. Pat. No. 4,176,188 which in turn is adivisional of Ser. No. 742,940 filed Nov. 18, 1976 now U.S. Pat. No.4,102,895.

The present invention relates to pharmacologically-active compounds andto processes for preparing them. The compounds which are the subject ofthis invention are represented by the formulae: ##STR1## wherein R₁ andR₂ are each --XY wherein X is hydrogen or hydroxy provided that when Xis hydrogen Y is hydrogen; methyl; hydroxy; lower alkoxy wherein thealkoxy group is straight or branched chain and contains 1-8 carbonatoms; cycloalkoxy wherein the cycloalkyl group contains 3-6 carbonatoms; phenoxy; substituted phenoxy wherein the substituent is nitro,halo or lower alkyl having 1-5 carbon atoms; trialkylsilyloxy whereinthe alkyl group contains 1-5 carbon atoms; heterocycloalkyloxy whereinthe hetero atom is nitrogen, oxygen or sulfur and the cycloalkyl groupcontains 4-5 carbon atoms; --OCOR' wherein R' is straight or branchedchain lower alkyl containing 1-8 carbon atoms, cycloalkyl containing 3-6carbon atoms, phenyl, substituted phenyl wherein the substituent isnitro, halo, lower alkyl wherein the alkyl group contains 1-5 carbonatoms, hydroxy, lower alkoxy wherein the alkoxy group contains 1-5carbon atoms, aryl such as phenyl and substituted phenyl wherein thesubstituent is nitro, halo or lower alkyl having 1-5 carbon atoms, andaryloxy such as phenoxy and substituted phenoxy wherein the substituentis nitro, halo or lower alkyl having 1-5 carbon atoms, provided that nomore than three substituents are present on the phenyl ring at any onetime; a sulfate, nitrate or phosphate radical; thiol; alkylthio whereinthe alkyl group contains 1-8 carbon atoms, arylthio such as phenylthioor substituted phenylthio wherein the substituent on the phenyl group isas defined above; halo; amino; alkylamino wherein the alkyl groupcontains 1-8 carbon atoms; dialkylamino wherein the alkyl group contains1-8 carbon atoms; arylamino such as phenylamino or substitutedphenylamino wherein the substituent is as defined above; --NH--CO--Qwherein Q is hydrogen, lower alkyl containing 1-8 carbon atoms, phenylor substituted phenyl wherein the substituent is nitro, halo or loweralkyl having 1-5 carbon atoms; --OCONHR wherein R is hydrogen or analkyl group containing 1-8 carbon atoms; and when X is hydroxy, Y iscyano; straight or branched chain lower alkyl, lower alkenyl or loweralkynyl wherein the alkyl group contains 1-8 carbon atoms and thealkenyl and alkynyl groups contain 2-8 carbon atoms; propadienyl;benzyl; substituted benzyl wherein the substituent is nitro, halo orlower alkyl having 1-5 carbon atoms; phenyl; substituted phenyl whereinthe substituent on the phenyl group is as defined above; provided thatwhen d or e is unsaturated, R₁ and R₂ are either X or Y; also within thescope of the invention are the quaternary ammonium salts and thepharmaceutically acceptable acid addition salts thereof such as thehydrochlorides or hydrobromides, for example.

R₁ and/or R₂ are oxo; thioxo, hydroxyimino; alkoxyimino wherein thealkoxy group contains 1-8 carbon atoms; aryloxyimino such asphenyloxyimino or substituted phenyloxyimino wherein the substituent onthe phenyl group is as defined above; acyloxyimino wherein the acylgroup is derived from a lower alkanoic acid having 1-8 carbon atoms oran aromatic acid such as benzoic acid or substituted benzoic acidwherein the substituent is nitro, halo or a lower alkyl group having 1-5carbon atoms, for example; hydrazono; alkylhydrazono, ordialkylhydrazono wherein the alkyl group contains 1-8 carbon atoms;arylhydrazono such as phenyl-hydrazono or substituted phenylhydrazonowherein the substituent on the phenyl group is as defined above;arylsulfonyl-hydrazono such as phenylsulfonylhydrazono or substitutedphenylsulfonylhydrazono wherein the substituent on the phenyl group isas defined above; carbamoylhydrazono; ethylenedioxy; ethylenedithio;ethylenethiooxy; dialkoxy such as dimethoxy, diethoxy, dibutoxy and thelike; thiazolidinyl; methylenyl; alkylidenyl wherein the alkyl groupcontains 2-8 carbon atoms; alkylimino wherein the alkyl group contains1-8 carbon atoms; or arylimino such as phenylimino and substitutedphenylimino wherein the substituent on the phenyl group is as definedabove;

R₃ is --CHXY wherein X is hydrogen or hydroxy provided that when X ishydrogen Y is hydrogen; methyl; hydroxy; lower alkoxy wherein the alkoxygroup is straight or branched chain and contains 1-8 carbon atoms;cycloalkoxy wherein the cycloalkyl group contains 3-6 carbon atoms;phenoxy, substituted phenoxy wherein the substituent is nitro, halo orlower alkyl having 1-5 carbon atoms; trialkylsilyloxy wherein the alkylgroup contains 1-5 carbon atoms; heterocycloalkoxy wherein the heteroatom is nitrogen, oxygen or sulfur and the cycloalkyl group contains 4-5carbon atoms; --OCOR' wherein R' is straight or branched chain loweralkyl containing 1-8 carbon atoms, cycloalkyl containing 3-6 carbonatoms, phenyl or substituted phenyl wherein the substituent on thephenyl group is as defined above; a sulfate, nitrate or phosphateradical; thiol; alkylthio wherein the alkyl group contains 1-8 carbonatoms; arylthio such as phenylthio or substituted phenylthio wherein thesubstituent on the phenyl group is as defined above; halo; amino;alkylamino wherein the alkyl group contains 1-8 carbon atoms;dialkylamino wherein the alkyl group contains 1-8 carbon atoms;arylamino such as phenylamino or substituted phenylamino wherein thesubstituent on the phenyl group is as defined above; --NH--CO--Q whereinQ is hydrogen, lower alkyl containing 1-8 carbon atoms, phenyl orsubstituted phenyl wherein the substituent is nitro, halo or lower alkylhaving 1-5 carbon atoms; --OCONHR wherein R is hydrogen or an alkylgroup containing 1-8 carbon atoms; and the quaternary ammonium salts andthe pharmaceutically acceptable acid addition salts thereof; and when Xis hydroxy, Y is cyano; straight or branched chain lower alkyl, loweralkenyl or lower alkynyl wherein the alkyl group contains 1-8 carbonatoms and the alkenyl and alkynyl groups contain 2-8 carbon atoms;propadienyl; benzyl; phenyl; substituted phenyl wherein the substituenton the phenyl group is as defined above; and R₃ is --CHZ wherein Z isoxo; thioxo; hydroxyimino; alkoxyimino wherein the alkoxy group contains1-8 carbon atoms; aryloxyimino such as phenyloxyimino or substitutedphenyloxyimino wherein the substituent on the phenyl group is as definedabove; acyloxyimino wherein the acyl group is derived from a loweralkanoic acid or an aromatic acid; hydrazono; alkyl-hydrazono ordialkylhydrazono wherein the alkyl group contains 1-8 carbon atoms;arylhydrazono such as phenylhydrazono or substituted phenylhydrazonowherein the substituent on the phenyl group is as defined above;arylsulfonylhydrazono such as phenylsulfonylhydrazono or substitutedphenylsulfonylhydrazono wherein the substituent on the phenyl group isas defined above; carbamoylhydrazono; ethylenedioxy; ethylenedithio;ethylenethiooxy; dialkoxy such as dimethoxy, diethoxy, dibutoxy and thelike; thiazolidinyl; methylenyl; alkylidenyl wherein the alkyl groupcontains 2-8 carbon atoms; alkylimino wherein the alkyl group contains1-8 carbon atoms; or arylimino such as phenylimino and substitutedphenylimino wherein the substituent on the phenyl group is as definedabove; and R₃ is carboxy; --COOR' wherein R' is as defined above; --COR"wherein R" is amino, alkylamino, or dialkylamino wherein the alkyl groupcontains 1-8 carbon atoms or arylamino such as benzamino or substitutedbenzamino wherein the substituent on the phenyl group is as definedabove, halo, hydrazino, alkylhydrazino or dialkylhydrazino wherein thealkyl group contains 1-8 carbon atoms, arylhydrazino such asphenylhydrazino or substituted phenylhydrazino wherein the substituenton the phenyl group is as defined above, arylsulfonylhydrazino such asphenylsulfonylhydrazino for example, or substitutedphenylsulfonylhydrazino wherein the substituent is as defined above;cyano; and ammonium, alkali metal and alkaline earth metal salts thereofwhere R₃ is carboxy;

R₄ is hydrogen, methyl or methylenyl;

R₅ is hydrogen, hydroxy, hydroperoxy or --OCOR'" wherein R'" is loweralkyl containing 1-8 carbon atoms;

R₆ is methylenyl when g is unsaturated, and when g is saturated R₆ is--CHXY wherein X is hydrogen or hydroxy, provided that when X ishydrogen Y is hydrogen; methyl; hydroxy; lower alkoxy wherein the alkoxygroup is straight or branched chain and contains 1-8 carbon atoms;cycloalkoxy wherein the cycloalkyl group contains 3-6 carbon atoms;phenoxy; substituted phenoxy wherein the substituent is nitro, halo orlower alkyl having 1-5 carbon atoms; trialkylsilyloxy wherein the alkylgroup contains 1-5 carbon atoms; heterocycloalkyloxy wherein the heteroatom is nitrogen, oxygen or sulfur and the cycloalkyl group contains 4-5carbon atoms; --OCOR' wherein R' is straight or branched chain loweralkyl containing 1-8 carbon atoms, cycloalkyl containing 3-6 carbonatoms, phenyl, substituted phenyl wherein the substituent on the phenylgroup is as defined above for R₁ and R₂ equals --XY; a sulfate, nitrateor phosphate radical; thiol; alkylthio wherein the alkyl group contains1-8 carbon atoms; arylthio such as phenylthio or substituted phenylthiowherein the substituent on the phenyl group is as defined above; halo;amino; alkylamino wherein the alkyl group contains 1-8 carbon atoms;dialkylamino wherein the alkyl group contains 1-8 carbon atoms;arylamino such as phenylamino or substituted phenylamino wherein thesubstituent on the phenyl group is as defined above, and the quaternaryammonium and acid addition salts thereof; --NH--CO--Q wherein Q ishydrogen, lower alkyl containing 1-8 carbon atoms, phenyl or substitutedphenyl; --OCONHR wherein R is hydrogen or an alkyl group containing 1-8carbon atoms; and when X is hydroxy, Y is cyano; straight or branchedchain lower alkyl, lower alkenyl or lower alkynyl wherein the alkylgroup contains 1-8 carbon atoms and the alkenyl or alkynyl groupscontain 2-8 carbon atoms; propadienyl; benzyl; substituted benzylwherein the substituent on the benzyl group is as defined above; phenyl;substituted phenyl wherein the substituent on the phenyl group is asdefined above; and R₆ is --CHZ wherein Z is oxo; thioxo; hydroxyimino;alkoxyimino wherein the alkoxy group contains 1-8 carbon atoms;aryloxyimino such as phenyloxyimino or substituted phenyloxyiminowherein the substituent on the phenyl group is as defined above;acyloxyimino wherein the acyl group is derived from a lower alkanoicacid having 1-8 carbon atoms or an aromatic acid such as benzoic acid,or a substituted benzoic acid, for example, hydrazono; alkylhydrazonowherein the alkyl group contains 1-8 carbon atoms; arylhydrazono such asphenylhydrazono or substituted phenylhydrazono wherein the substituenton the phenyl group is as defined above; arylsulfonylhydrazono such asphenylsulfonylhydrazono or substituted phenylsulfonylhydrazono whereinthe substituent on the phenyl group is as defined above;carbamoylhydrazono; ethylenedioxy; dialkoxy such as dimethoxy, diethoxy,dibutoxy and the like; ethylenedithio; ethylenethiooxy; thiazolidinyl;methylenyl; alkylidenyl wherein the alkyl group contains 2-8 carbonatoms; alkylimino wherein the alkyl group contains 1-8 carbon atoms; orarylimino such as phenylimino and substituted phenylimino wherein thesubstituent on the phenyl group is as defined above; and R₆ is carboxy;--COOR' wherein R' is as defined above; --COR" wherein R" is amino,alkylamino or dialkylamino wherein the alkyl group contains 1-8 carbonatoms; arylamino such as benzamino or substituted benzamino wherein thesubstituent on the phenyl group is as defined above, halo, hydrazino,alkylhydrazino or dialkylhydrazino wherein the alkyl group contains 1-8carbon atoms, arylhydrazino such as phenylhydrazino or substitutedphenylhydrazino wherein the substituent on the phenyl group is asdefined above, arylsulfonylhydrazino such as phenylsulfonylhydrazino,and substituted phenylsulfonylhydrazino, for example; cyano; andammonium, alkali metal and alkaline earth metal salts thereof where R₆is carboxy;

R₇ is hydrogen, hydroxy, lower alkoxy wherein the alkoxy group contains1-8 carbons or --OCOR'" wherein R'" is lower alkyl containing 1-8 carbonatoms; and

R₈ is --COOH and the ammonium, alkali metal and alkaline earth metalsalts thereof; --CH₂ OH; --CHO; cyano; --COOR' wherein R' is as definedabove; --COCl or --CONH₂ ; and n is an integer from 0-5.

Excluded from Formula I are those compounds wherein n is 0 and a and care unsaturated, b, d, e and f are saturated, R₁ is oxo, R₂ is --XYwherein X and Y are hydrogen and hydroxy, R₃ is --CH₂ OH and R₄ ishydrogen and those compounds wherein n is 0, a and b are unsaturated, c,d, e and f are saturated, R₁ is oxo, R₂ is --XY wherein X and Y arehydrogen and hydroxy, R₃ is --CH₂ OH, R₄ is methyl and R₅ is hydrogenwhen the carbon at the 3 position has the R configuration and theorientation at the a double bond has the E configuration.

Preferred among the compounds of the present invention are thosecompounds of the formulae: ##STR2## wherein R₁ and R₂ are each --XYwherein X is hydrogen or hydroxy provided that when X is hydrogen, Y ishydrogen; methyl; hydroxy; lower alkoxy; cycloalkoxy; heterocycloalkoxy;phenoxy; substituted phenoxy; --OCOR' wherein R' is lower alkyl,cycloalkyl, phenyl and substituted phenyl; halo; amino; alkylamino;dialkylamino; and when X is hydroxy, Y is lower alkyl; lower alkenyl;lower alkynyl; benzyl; substituted benzyl; phenyl; substituted phenyl;provided that when d or e is unsaturated R₁ and R₂ are either X or Y;and R₁ and/or R₂ are oxo; hydroxyimino or dialkoxy;

R₃ is --CHXY wherein X is hydrogen or hydroxy provided that when X ishydrogen, Y is hydrogen; methyl; hydroxy; lower alkoxy; cycloalkoxy;heterocycloalkoxy; phenoxy; substituted phenoxy; --OCOR' wherein R' islower alkyl, cycloalkyl, phenyl or substituted phenyl; halo; amino;alkylamino; dialkylamino; and when X is hydroxy, Y is lower alkyl; loweralkenyl; lower alkynyl; benzyl; substituted benzyl; phenyl; substitutedphenyl; and R₃ is --CHZ, wherein Z is oxo, hydroxyimino or dialkoxy; andR₃ is carboxy; --COOR' wherein R' is as defined above; and ammonium,alkali metal and alkaline earth metal salts thereof where R₃ is carboxy;

R₄ is hydrogen, methyl or methylenyl;

R₅ is hydrogen; hydroxy; hydroperoxy; or --OCOR'" wherein R'" is loweralkyl;

R₆ is methylenyl when g is unsaturated, and when g is saturated R₆ is--CHXY wherein X is hydrogen, or hydroxy, provided that when X ishydrogen, Y is hydrogen; methyl; hydroxy; lower alkoxy, cycloalkoxy;phenoxy; substituted phenoxy; --OCOR' wherein R' is as defined above;halo; amino; alkylamino; dialkylamino; and when X is hydroxy, Y is loweralkyl; lower alkenyl; lower alkynyl; benzyl; substituted benzyl; phenyl;substituted phenyl; and R₆ is --CHZ wherein Z is oxo, hydroxyimino ordialkoxy; or R₆ is carboxy; --COOR' wherein R' is as defined above; andammonium, alkali metal and alkaline earth metal salts thereof where R₆is carboxy;

R₇ is hydrogen; hydroxy; lower alkoxy; or --OCOR'" wherein R'" is loweralkyl;

R₈ is --COOR' wherein R' is as defined above or --COOH and the ammoniumand alkali metal and alkaline earth metal salts thereof; and n is aninteger from 0-5, provided that in formula I C₃ does not have the Rconfiguration and the double bond at a does not have the E configurationwhen n=0, a and c are unsaturated, b, d, e and f are saturated, R₁ isoxo, R₂ is --XY wherein X and Y are hydrogen and hydroxy, R₃ is --CH₂ OHand R₄ is hydrogen and when n=0, a and b are unsaturated, c, d, e and fare saturated, R₁ is oxo, R₂ is --XY wherein X and Y are hydrogen andhydroxy, R₃ is --CH₂ OH, R₄ is methyl and R₅ is hydrogen.

As can be seen from the above structures, the side chains extending fromthe 2 and 6 positions of the oxepane ring may be either saturated andunsaturated. In addition, the bond between carbons 3 and 4 of the ringmay also be saturated or unsaturated. The points of unsaturation on thering and side chains are indicated by the letters a, b, c, d, e, f andg. However, when there is a double bond at b, there is no double bond atc, d and f. When a is unsaturated, the configuration around the a doublebond may be either E or Z. It is understood therefore, unless otherwisestated, tht when the starting material in a given example has a 6Econfiguration, the product will have a 6E configuration and when thestarting material has a 6Z configuration, the product will also have a6Z configuration. The carbon at the 3 position may have either the R orthe S configuration.

Also within the scope of the invention are those compounds having anepoxide ring in either side chain as illustrated in Formula II. Althoughseveral epoxide rings are illustrated in Formula II, at no time is theremore than one epoxide bridge in the side chain at the 2 position of theoxepane ring. Those compounds having an oxygen bridge between carbons 3and 6 (Formula III) are also part of the present invention.

In U.S. Ser. No. 672,918, a method is described for obtaining discretecompounds from the zoapatle plant. The zoapatle plant is a bush about 2meters high that grows wild in Mexico. Botanically it is known asMontanoa tomentosa according to Cervantes, Fam. Compositae, TribeHeliantheae; another variety of the species is Montanoa floribunda. Theplant is described in great detail in Las Plantas Medicinales de Mexico,third edition, Ediciones Botas (1944).

The plant has been used for centuries in the form of a "tea" or othercrude aqueous preparations primarily as a labor inducer for humans. Itsuse as a utero-evacuant agent has been documented in the literature, butdefinitive chemical and pharmacological studies have not been described.By utero-evacuant is meant an agent which causes the uterus of warmblooded animals to contract or expel its contents. Such agents aregenerally employed to induce menses, expel a hydratiform mole, expel orresorb a fetus, induce abortion or delayed labor and in situations inwhich the contents of the uterus, such as the fetus or placenta, shouldbe evacuated.

As a result of the purification steps described in Ser. No. 672,918, twodiscrete compounds are isolated. One of the compounds is2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oland the other is2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol.These compounds are the starting materials for the novel compounds ofthis invention and are not part of the present invention.

The following schematic diagram illustrates general methods forpreparing the monocyclic and bicyclic compounds of the present inventionfrom the naturally occurring substances. The starting materials aredesignated by the numbers 1 to 25 while the other numbers refer tospecific examples which are fully illustrated below. The lettersdesignate the specific reagent or reagents employed in the reaction.Although a compound having an E configuration at the 6 position may beprepared by a given example, it should be understood that the sameprocess may be employed for compounds having a Z configuration at the 6position. As can be seen from the diagram, the intermediate compoundsformed by the illustrated processes may be used as starting materialsfor other compounds. However, the end products and the intermediatesboth possess useful activity. ##STR3##

The compounds of this invention are prepared by using the naturallyoccurring compounds as the starting material. The compounds that areprepared for a given series are generally employed as the startingmaterials for all of the other compounds in that series.

Those compounds wherein n is equal to or greater than 1 are prepared byreacting an appropriately substituted compound having an acyl halidegrouping in the 6 position with diazomethane in an appropriate solvent.Suitable solvents include diethyl ether, tetrahydrofuran, dioxane andthe like. The resulting diazoketone is then rearranged to the homologousacid. The length of the side chain can be further increased byconverting the acid thus obtained to the acid halide and reacting theacid halide with diazomethane as described above. In this way the lengthof the side chain can be increased to the desired length.

Those compounds of Formula II having an epoxide ring on either of theside chains are prepared by reacting the unsaturated compound with aperacid such as, for example, m-chloroperoxybenzoic acid, or by reactionwith vanadylacetylacetonate/t-butyl hydroperoxide or hydrogenperoxide/sodium hydroxide.

Those compounds of Formula IV are prepared by reacting the appropriatelysubstituted compound of Formula I having an unsaturated double bond at awith an oxidizing reagent such as, for example, Jones reagent in anappropriate solvent. Suitable solvents include acetone, 2-butanone andthe like.

Those compounds of Formula III having an oxygen bridge between carbons 3and 6 are prepared by reacting those compounds of Formula I wherein R₂or R₃ is hydroxy or oxo, a is unsaturated, n=0 with an appropriate agentsuch as p-toluenesulfonic acid, manganese dioxide and platinumoxide/sodium bicarbonate, for example. These reactions are carried outin a suitable solvent, such as benzene, toluene, xylene and the like.The reactions are generally carried out at room temperature althoughelevated temperatures may be employed in some cases.

The initial extract from which the purified materials are obtained isprepared from the zoapatle plant through a series of extraction andpurification steps. These procedures are described in detail in Ser. No.672,918. The material obtained as a result of this purificationprocedure is a mixture containing at least three components as evidencedby gas chromatography. The presence of utero-evacuant materials in themixture is determined through the use of procedures employed for thedetection of uterine contractions and interruption of pregnancy infemale animals.

The compounds of the present invention have also been found to possessutero-evacuant properties. There are effective in inducing uterinecontractions when administered in doses ranging from about 0.25 mg./kg.to about 100 mg./kg. The compounds are effective in interruptingpregnancy at dosage levels between about 2.5 mg./kg. and 400 mg./kg. Theactual dosage employed will depend upon the species of animal to whichthe compound is administered. The compounds can be administered informulations prepared according to acceptable pharmaceutical practices.Suitable formulations include solutions, suspensions and solid dosageforms in pharmaceutically acceptable carriers. They can be administeredperorally or intravenously or in any conventional manner in accordancewith acceptable pharmaceutical practices.

In addition to their activity as utero-evacuants, many of the compoundsof the present invention have been found to possess useful activity ascentral nervous system depressants. Activity at doses as low as 3.7mg./kg. has been observed.

The following describes the invention in greater particularity and isintended to be a way of illustrating but not limiting the invention.

EXAMPLE 12S,3R-6E-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol##STR4##

The crude extract obtained by extracting the leaves of the zoapatleplant (50 g.) is dissolved in ether (5 l.) and the resulting solution isfiltered and washed with saturated sodium bicarbonate solution (500ml.). The ether is dried over anhydrous sodium sulfate, filtered andconcentrated to dryness to afford a light yellow oil (44.6 g.). This oilis then dissolved in chloroform (400 ml.) and the solution added to acolumn (4 in.×4 ft.) of 2.5 kg. of neutral silicic acid packed inchloroform. The column is eluted with chloroform, chloroform-isopropanolmixtures, and fractions are collected. The fractions are evaporated todryness in vacuo at a temperature below 40° C. The column is eluted asfollows:

    ______________________________________                                                 Volume/                                                                       Fraction                                                             Fraction (ml.)        Eluent                                                  ______________________________________                                         1-7     650          CHCl.sub.3                                               8-30    500          isopropanol:CHCl.sub.3 (1:41.7)                         31-60    500          isopropanol:CHCl.sub.3 (1:33.3)                         61-105   500          isopropanol:CHCl.sub.3 (1:28.6)                         ______________________________________                                    

The composition of the fractions is monitored by thin layerchromatography [silica gel, isopropanol-chloroform (1:12.5) ] and by gaschromatography--3% OV17 [methyl silicone--phenyl silicone (1:1)] columnusing a programmed run (150°-250°). Fractions Nos. 78-84 are combinedand the solvent removed in vacuo to afford an oily residue (5.1 g.)which contains at least three components as indicated by gaschromatography.

A portion of the residue (3.2 g.) is then dissolved in benzene (50 ml.)and the solution added to a column (4 in.×35 in.) packed with 2 kg. ofOR-PVA Merck-O-Gel 2000* prepared in benzene. The column is eluted withbenzene. Thin layer chromatography and gas chromatography are used tomonitor the composition of the fractions.

    ______________________________________                                                      Volume/                                                                       Fraction                                                               Fraction                                                                             (ml.)                                                           ______________________________________                                               1-7    1000                                                                   8-45    300                                                            ______________________________________                                    

Fractions 23-33 contain 1.73 g. (54%) of the applied material.

Fraction 31 is evaporated to give2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olas an oil (0.326 g.) having the following spectral characteristics:

I.R. (Neat) μ: 2.91 and 5.88; N.M.R. _(TMS) ^(CDCl).sbsp.3 δ: ##STR5##

Mass Spec. [m/e]: 320 [M-18], 251, 233, 221, 171, 143, 141, 137, 125,113, 97, 95, 81, 69;

Chemical Ionization: M⁺ +H=339;

M.W.=338

EXAMPLE 22S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(500 mg.) in dry pyridine (6 ml.) is treated, while stirring at roomtemperature under nitrogen, with acetic anhydride (3 ml.). Afterstirring 18 hrs. at room temperature, the mixture is evaporated todryness in vacuo, treated with methanol (1 ml.) and again evaporated indryness in vacuo. The residue is chromatographed on a SilicAR column,using ethyl acetatecyclohexane (1:20) as the eluting solvent. The lesspolar fraction is eluted to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(200 mg.):

I.R. (Neat) μ, 5.75, 5.83 and 6.2;

NMR _(TMS) ^(CDCl).sbsp.3 δ: 1.06 (d, J=7 Hz, 3H, --CH--CHHD 3); 1.14(s, 3H, --O--C--CHHD 3); 1.60 and 1.70 [each s, 3H, HC═C--(CHHD 3)₂ ];2.03 (s, 6H, --OCO--CHHD 3); 3.11 ##STR6## 4.08 (s, 2H, CHHD 2--O--C),4.60 (d, J=8 Hz, 2H, C═CH--CHHD 2--OAc); 4.80 (m, 1H, CHOAc); 5.1-5.5(m, 2H, (CH₃)₂ --C═CH C═CH13 CH₂ --OAc).

When in the above procedure propionic anhydride and benzoic anhydrideare employed in place of acetic anhydride, the corresponding propionateand benzoate esters are obtained.

The following compounds are prepared according to the procedure ofExample 2 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    __________________________________________________________________________     ##STR7##                                                                     R.sub.1  R.sub.2    R.sub.3       R.sub.4                                                                           R.sub.5                                                                          a b c                                __________________________________________________________________________    O        OCOC.sub.6 H.sub.4 pNO.sub.2                                                             CH.sub.2OCOC.sub.6 H.sub.4 pNO.sub.2                                                        H   -- u s u                                O        O          CH.sub.2OCOC.sub.6 H.sub.5                                                                  H   -- u s u                                OCOC.sub.3 H.sub.7                                                                     O          CHO           H   -- u s u                                OCOC.sub.6 H.sub.4 pBr                                                                 O          CH.sub.2OCOC.sub.6 H.sub.4 pBr                                                              H   -- u s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CH.sub.2OCOC.sub.6 H.sub. 5                                                                 H   -- u s u                                O        OCOC.sub.5 H.sub.11                                                                      CH.sub.2 OCOC.sub.5 H.sub.11                                                                CH.sub.3                                                                          H  u u s                                O        OAc        CH.sub.2 OAc  H   H  s s s                                O        OCOC.sub.6 H.sub.5                                                                       CH.sub.2OCOC.sub.6 H.sub.5                                                                  CH.sub.3                                                                          H  s s s                                O        OAc        CH.sub.2 OAc  H   -- s s u                                O        OAc        CH.sub.2 OAc  H   H  u s s                                O        OAc        CH.sub.2 OAc  CH.sub.3                                                                          H  s u s                                O        OCOC.sub.3 H.sub.7                                                                       CH.sub.2 OCOC.sub.3 H.sub.7                                                                 CH.sub.3                                                                          H  u s s                                O        OAc        CH.sub.2 OAc  H   H  u u s                                O        OAc        CH.sub.2OAc   CH.sub.3                                                                          -- u s u                                O        OAc        CH.sub.2OAc   CH.sub.2                                                                          H  u s s                                O        OAc        CH.sub.2OAc   CH.sub.3                                                                          -- s s u                                O        OCOC.sub.6 H.sub.5                                                                       CH.sub.2Br    H   -- u s u                                O        OAc        CH.sub.2SH    H   -- u s u                                 ##STR8##                                                                              OAc        CH.sub.2 OAc  H   -- u s u                                  O      OH         CH.sub.2 OCOC.sub.6 H.sub.5                                                                 H   -- u s u                                 ##STR9##                                                                              OAc        CH.sub.2OAc   H   -- u s u                                 ##STR10##                                                                             OAc        CH.sub.2OAc   H   -- u s u                                  O      OAc        CH.sub.2OAc   H   OH u u s                                O        OAc        CH.sub.2 OTHP H   -- u s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CH.sub.2 OAc  H   -- u s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CO.sub.2 H    H   -- s s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CO.sub.2 CH.sub.3                                                                           H   -- s s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CO.sub.2 Na   H   -- s s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CONH.sub.2    H   -- s s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CONHNH.sub.2  H   -- s s u                                OCOC.sub.6 H.sub.5                                                                     OCOC.sub.6 H.sub.5                                                                       CN            H   -- s s u                                __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 2 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR11##                                                                      R.sub.1         R.sub.2     R.sub.3                                                                             R.sub.4                                                                            b   c                                ______________________________________                                        OAc           CH.sub.2    H       --   s   u                                  OCOC.sub.6 H.sub.5                                                                          CH.sub.2    CH.sub.3                                                                              H    u   s                                  OCOC.sub.6 H.sub.4 pNO.sub.2                                                                CH.sub.3    H       H    s   s                                   ##STR12##    CH.sub.3    CH.sub.3                                                                              H    s   s                                    OCOC.sub.6 H.sub.13                                                                       CH.sub.2    H       H    u   s                                  OCOC(CH.sub.3).sub.3                                                                        CH.sub.2    CH.sub.2                                                                              H    s   s                                  OAc           CH.sub.2    CH.sub.3                                                                              --   s   u                                  OCOC.sub.6 H.sub.4 pBr                                                                      CH.sub.3    H       --   s   u                                  OCOCH.sub.2C.sub.6 H.sub.5                                                                  CH.sub.2    H       H    s   s                                  OCOC.sub.4 H.sub.9                                                                          CH.sub.3    H       H    u   s                                  OCOC.sub.3 H.sub.7                                                                          CH.sub.3    CH.sub.2                                                                              H    s   s                                  OCOC.sub.5 H.sub.11                                                                         CH.sub.3    CH.sub.3                                                                              --   s   u                                  OCOC.sub.2 H.sub.5                                                                          CH.sub.2    CH.sub.3                                                                              H    s   s                                  OAc           CH.sub.3    CH.sub.3                                                                              H    u   s                                  O             CH.sub.2OAc H       --   s   u                                  OAc           CH.sub.2OAc H       --   s   u                                  OAc           CHO         H       --   s   u                                  OAc           CO.sub.2 H  H       --   s   u                                  OCOC.sub.6 H.sub.5                                                                          CO.sub.2 CH.sub.3                                                                         H       --   s   u                                  OAc           CN          H       --   s   u                                  OAc           CONH.sub.2  H       --   s   u                                  OAc           CONH.sub.2  H       H    s   s                                  OAc           CONHC.sub.6 H.sub.5                                                                       H       --   s   u                                   ##STR13##    CH.sub.2 OAc                                                                              H       --   s   u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 32S,3R-6-(2-Acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol

A sample of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(2.6 g.) is dissolved in benzene (200 ml.) and pyridine (20 ml.). Thesolution is cooled to 0° under nitrogen and treated with an excess ofacetyl chloride (15 ml.) during a 15 min. period. The mixture is allowedto stir for 2 hrs. followed by the addition of ether (300 ml.). Theorganic layer is washed with saturated cupric sulfate solution (3×200ml.), dried (MgSO₄) and evaporated in vacuo to give a brown oil.

The oil is chromatographed on a SilicAr column using ether:petroleumether (2:3) as the eluting solvent. The less polar fraction is eluted toafford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(1.3 g.) and the more polar fraction is eluted to afford2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(1.1 g.):

I.R. (Neat) 2.86 (br), 5.76 (s), 5.83 (s), 8.0μ (s);

N.M.R. _(TMS) ^(CDCl).sbsp.3 δ: 5.3 [m, 2H, (CH₃)₂ C═CH, C═CH --CH₂OAc], 4.6 (d, J=7 Hz, 2H, C═CH--CH₂ OAc), 4.05 ##STR14##

3.1 [bd, J=7 Hz, 2H, (CH₃)₂ C═CCHHD 2CO].

When in the above procedure benzoyl chloride, propionyl chloride andpentanoyl chloride are employed in place of acetyl chloride, thecorresponding benzoate, propionate and pentanoate esters are obtained.

EXAMPLE 42S-6-(2-Acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

A solution of2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(350 mg) in methylene chloride (2 ml) is added to a solution ofpyridinium chlorochromate (338 mg) in methylene chloride (1.5 ml) atroom temperature. The mixture is stirred for 2 hours and treated withether (100 ml). The resulting mixture is filtered through a pad ofcelite and the solvent removed in vacuo to give an oily residue which ispurified on preparative tlc plates (2:5, ethyl acetate:chloroform) togive2S-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(0.195 g):

IR (neat) μ: 5.74 (OCOCH₃) and 5.85 (C═O); NMR (CDCl₃ -TMS) δ: 1.06 (d,J=7 Hz, 3H, CHHD 3--CH), 1.23 (s, 3H, CHHD 3--C--), 2.03 (s, 3H, OCOCHHD3), 3.09 (d, J=7 Hz, 2H, CHHD 2CO--), 4.03 (s, 2H, O--CHHD 2--), 4.56(d, J=7 Hz, 2H, CHHD 2--OAc).

EXAMPLE 52S,6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

A solution of2S,6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(378 mg.) in methanol (10 ml.) is treated at 0° with potassium carbonate(200 mg.) in water (10 ml.) for 2.5 hrs. The reaction mixture is dilutedwith water and extracted with ether. Removal of the solvent in vacuoaffords2S,6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

The following compounds are prepared by the method of Example 5 bysubstituting an equivalent amount of the appropriate starting materialfor2S,6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR15##                                                                        R.sub.4    R.sub.5    a      b      c                                     ______________________________________                                        CH.sub.3   H          u        u      s                                       H          H          s        s      s                                       CH.sub.3   H          s        s      s                                       H          --         s        s      u                                       H          H          u        s      s                                       CH.sub.3   H          s        u      s                                       CH.sub.3   H          u        s      s                                       H          H          u        u      s                                       CH.sub.2   H          u        s      s                                       CH.sub.3   --         u        s      u                                       H          H          s        u      s                                       CH.sub.2   H          s        s      s                                       CH.sub.3   --         s        s      u                                       H          OH         u        u      s                                       H          OH         s        s      s                                       H          OH         s        u      s                                       ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2  -- O                                                                 R.sub.3 -- CH.sub.2 OH                                                        u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 62S,3R-3-Acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(300 mg.) in methanol (8 ml.) is treated at 0° C. with potassiumcarbonate (160 mg.) in water (8 ml.) for 4 hrs. The reaction mixture isdiluted with water (160 ml.) and extracted with ether (240 ml.). Theorganic layer is dried and the solvent removed in vacuo to give an oilyresidue (˜260 mg.).

The residue is plate chromatographed on silica gel, using ethylacetate-hexane (1:1) as the developing solvent. The major band is elutedwith ethyl acetate to afford2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(144 mg.)

I.R. (Neat) μ: 2.9, 5.75 and 5.85;

N.M.R. _(TMS) ^(CDCl).sbsp.3 δ: 1.05 (d, J=7 Hz, 3H, CH--CH₃), 1.11 (s,3H, --O--C--CH₃), 1.61 and 1.73 [each s, each 3H, (CH₃)₂ --C═CH], 2.01(s, 3H, --O--CO--CH₃), 3.09 (d, J=7 Hz, 2H, --CH₂ --CO), 4.06 ##STR16##4.13 (d, J=8 Hz, 2H, ═CH--CHHD 2--OH), 4.61-4.83 (m, 1H, CH13 OAc),5.23-5.50 [m, 2H, (CH₃)₂ --C═CH0 and ═CH13 CH₂ OH].

EXAMPLE 72S,3R-3-Acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A. A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(400 mg.) in methylene chloride (100 ml.) is treated with manganesedioxide (1.2 g.) at room temperature under nitrogen for 17 hrs. Themanganese dioxide is filtered and washed with methylene chloride and thesolvent is removed in vacuo to give an oil (400 mg.).

This oil is plate chromatographed on silica gel, using ethylacetate-hexane (2:3) as the developing solvent. The major band is elutedwith ethyl acetate to afford2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(230 mg.):

I.R. (Neat) μ: 5.75, 5.80 and 5.97;

N.M.R. _(TMS) ^(CDCl).sbsp.3 δ: 1.06 (d, J=7 Hz, 3H, CH--CHHD 3); 1.11(s, 3H, C--O--C--CHHD 3); 1.60 (s, 3H, CH₃ --C═CH); 1.71 (s, 3H, CHHD3--C═CH); 2.06 (s, 3H, CO--CHHD 3); 3.09 (d, J=7 Hz, 2H, CHHD 2--CO);4.25 (s, 2H, --C--CHHD 2--O--C); 4.74 (m, 1H, CH13 OAc); 5.11-5.45 [m,1H, (CH₃)₂ --C═CH9 ; 5.81 (d, J=8 Hz, 1H, ═CH13 CHO); 9.95 [d, J=8 Hz,1H, (CH)]; UV (EtOH); 2.38 nm. (ε=10288)

B. Following the procedure of Example 4 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane)-3-ol,2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by method A of Example 7 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR17##                                                                         R.sub.4    R.sub.5   a      b      c                                     ______________________________________                                        CH.sub.3    H         u        u      s                                       H           H         u        s      s                                       CH.sub.3    H         u        s      s                                       H           H         u        u      s                                       CH.sub.2    H         u        s      s                                       CH.sub.3    --        u        s      u                                       H           OH        u        u      s                                       ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- OAc                                                                R.sub.3 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by method B of Example 7 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                        R.sub.4    R.sub.5    a        b      c                                       ______________________________________                                        H          H          s        s      s                                       CH.sub.3   H          s        s      s                                       H          --         s        s      u                                       CH.sub.3   H          s        u      s                                       H          H          s        u      s                                       ═CH.sub.2                                                                            H          s        s      s                                       CH.sub.3   --         s        s      u                                       H          --OH       s        s      s                                       H          --OH       s        u      s                                       ______________________________________                                    

EXAMPLE 82S,3R-3-Acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg.) in absolute ethanol (10 ml.) is treated with sodiumborohydride (60 mg.) at room temperature for 18 hrs. The solution isdiluted with water (5 ml.) followed by 5% hydrochloric acid until thesolution is neutral. The aqueous phase is extracted with methylenechloride and the organic phase is washed with saturated salt solution,dried and evaporated to give2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane.

EXAMPLE 92S,3R-3-Acetoxy-6-[2-tetrahydropyran-2-yloxy)-ethylidene)-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane

A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(382 mg.) in anhydrous benzene (3 ml.) is treated with dihydropyran (4.5ml.) and p-toluenesulfonic acid (2 mg.) under nitrogen. After 2 hrs. at25° C., the reaction mixture is washed with 10% sodium bicarbonatesolution, dried and evaporated to give2S,3R-3-acetoxy-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane.

EXAMPLE 102S,3R-6-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-ol

A solution of2S,3R-3-acetoxy-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane(550 mg.) in methanol (10 ml.) is treated with potassium carbonate (210mg.) in water (10 ml.) for 18 hrs. at 25° C. The reaction mixture isdiluted with water (150 ml.) and extracted with ether. The organic phaseis dried and evaporated to give2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl)]-oxepan-3-ol.

EXAMPLE 11 2S-6-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-one

A solution of2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-ol(508 mg.) in methylene chloride (35 ml.) and pyridine (1 ml.) is treatedwith chromium trioxide (625 mg.) and celite (1.5 g.). The resultingsuspension is stirred for 4 hrs. and filtered. The filter cake is washedwith methylene chloride and the filtrate evaporated. The filter cake isthen washed with ether, the filtrate is added to the residue obtainedfrom the evaporation of the methylene chloride, filtered throughadditional celite and the organic phase is treated with 10% sodiumbicarbonate solution and washed with a saturated salt solution, driedand evaporated to give2S-6-[2-tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-one.

EXAMPLE 122S-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one

A solution of2S-6-[2-(tetrahydropyran-2-yloxy)ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-one(500 mg.) in 70% acetic acid (100 ml.) is warmed on a steam bath for 2hrs. and then stirred at room temperature for 18 hrs. The solution isevaporated to dryness and the residue is dissolved in ether and treatedwith 5% sodium bicarbonate solution, washed with saturated saltsolution, dried and evaporated to give2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

The following compounds are prepared by the method of Example 12 bysubstituting an equivalent amount of the appropriate starting materialfor2S-6-[2-(tetrahydrofuran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-one.

    ______________________________________                                         ##STR18##                                                                         R.sub.4    R.sub.5   a      b      c                                     ______________________________________                                        CH.sub.3    H         u        u      s                                       H           H         s        s      s                                       CH.sub.3    H         s        s      s                                       H           --        s        s      u                                       H           H         u        s      s                                       CH.sub.3    H         s        u      s                                       CH.sub.3    H         u        s      s                                       H           H         u        u      s                                       CH.sub.2    H         u        s      s                                       CH.sub.3    --        u        s      u                                       H           H         s        u      s                                       CH.sub.2    H         s        s      s                                       CH.sub.3    --        s        s      u                                       H           OH        u        u      s                                       H           OH        s        s      s                                       H           OH        s        u      s                                       ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2  -- O                                                                 R.sub.3 -- CH.sub.2 OH                                                        u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 132S-6-(2-Oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one

A solution of2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one(338 mg.) in methylene chloride (30 ml.) is treated with manganesedioxide (150 mg.). After stirring at 25° C. for 18 hrs. under nitrogen,the resulting suspension is filtered, the filter cake washed withmethylene choride and the combined filtrate and washings evaporated togive2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

The following compounds are prepared by the method of Example 13 bysubstituting an equivalent amount of the appropriate starting method for2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR19##                                                                          R.sub.4    R.sub.5  a      b      c                                     ______________________________________                                        H            H        u        s      s                                       CH.sub.3     H        u        s      s                                       CH.sub.2     H        u        s      s                                       CH.sub.3     --       u        s      u                                       ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- O                                                                  R.sub.3 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 142S-6-(2-t-Butyldimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one

To a solution of2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one(338 mg.), pyridine (1 ml.) and ether (10 ml.) is addedt-butyldimethylsilyl chloride (170 mg.) at 0° under nitrogen. Themixture is allowed to warm to 25° C. and is stirred for 1 hr. Theresulting mixture is treated with ether (25 ml.) and water (20 ml.). Theorganic phase is separated, washed with saturated cupric sulfate (3×25ml.), dried and evaporated to afford2S-6-(2-t-butyldimethyl-siloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

EXAMPLE 152S-6-(2-t-Butyldimethylsiloxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 2 but substituting an equivalentamount of2S-6-(2-t-butyldimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-onefor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S-6-(2-t-butyldimethylsiloxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-oneis obtained.

EXAMPLE 162S-6-(2-Hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

A solution of2S-6-(2-t-butyldimethylsiloxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one(597 mg.) in 9:1 tetrahydrofuran:water (15 ml.) is treated with 80%acetic acid (10 ml.) at 25° C. for 2 hrs. The resulting solution isevaporated in vacuo and the residue is partitioned between ether andwater. The organic phase is washed with saturated salt solution, driedand evaporated to afford2S-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one.

EXAMPLE 172S-6-(2-Oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 11 but substituting an equivalentamount of2S-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-3-hydroxy-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane,2S-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-oneis obtained.

Following the procedure of Example 10 but substituting an equivalentamount of2S-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-3-acetoxy-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane,2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-oneis obtained.

The following compounds are obtained by the sequence outlined inExamples 14 through 17 by substituting an equivalent amount of theappropriate starting material for2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR20##                                                                         R.sub.4    R.sub.5   a      b      c                                     ______________________________________                                        CH.sub.3    H         u        u      s                                       H           H         s        s      s                                       CH.sub.3    H         s        s      s                                       H           --        s        s      u                                       CH.sub.3    H         s        u      s                                       H           H         u        u      s                                       H           H         s        u      s                                       CH.sub.2    H         s        s      s                                       CH.sub.3    --        s        s      u                                       H           OH        u        u      s                                       H           OH        s        s      s                                       H           OH        s        u      s                                       ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- O                                                                  R.sub.3 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 182S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol

2S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(700 mg.) is dissolved in absolute ethanol (20 ml.); sodium borohydride(115 mg.) is added slowly with stirring and the reaction mixture isstirred at room temperature for 18 hrs. The reaction is quenched byadding water (10 ml.) followed by 5% hydrochloric acid (˜3-5 ml.) untilthe solution is neutral. The aqueous phase is extracted with methylenechloride, filtered through phase-separating paper and the solventremoved in vacuo. The residue (660 mg.) is plate chromatographed onsilica gel using isopropanol-chloroform (1:9) as the developing solvent.The major band is eluted with isopropanol-chloroform (1:1) to afford2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol(424 mg.):

I.R. (Neat) μ: 2.95 and 6.0;

N.M.R._(CDCl).sbsb.3^(TMS) δ: 0.91 (d, J=5 Hz, 3H, --CH--CH₃); 1.14 (s,3H, --O--C--CH₃); 1.65 and 1.71 [each s, 6H, HC═C--(CH₃)₂ ]; 3.33-3.63(m, 2H, --CH--OH); 4.15 (d, J=6 Hz, 4H, C═CH--CH₂ --OH, --CH₂ --O--R);5.13-5.56 [multiplet, 2H, C═CH--CH₂ OH; (CH₃)₂ --C═CH ].

The following compounds are prepared by the method of Example 18 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR21##                                                                         R.sub.4    R.sub.5   a      b      c                                     ______________________________________                                        CH.sub.3    H         u        u      s                                       H           H         s        s      s                                       CH.sub.3    H         s        s      s                                       H           --        s        s      u                                       H           H         u        s      s                                       CH.sub.3    H         s        u      s                                       CH.sub.3    H         u        s      s                                       H           H         u        u      s                                       CH.sub.2    H         u        s      s                                       CH.sub.3    --        u        s      u                                       H           H         s        u      s                                       CH.sub.2    H         s        s      s                                       CH.sub.3    --        s        s      u                                       H           OH        u        u      s                                       H           OH        s        s      s                                       H           OH        u        s      s                                       H           OH        s        u      s                                       ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- OH                                                                 R.sub.3 -- CH.sub.2 OH                                                        u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the method of Example 18 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethyidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR22##                                                                         R.sub.2   R.sub.3    R.sub.4 b     c                                     ______________________________________                                        CH.sub.2   H          --        s     u                                       CH.sub.2   CH.sub.3   H         u     s                                       CH.sub.3   H          H         s     s                                       CH.sub.3   CH.sub.3   H         s     s                                       CH.sub.2   H          H         u     s                                       CH.sub.2   CH.sub.2   H         s     s                                       CH.sub.2   CH.sub.3   --        s     u                                       CH.sub.3   H          --        s     u                                       CH.sub.2   H          H         s     s                                       CH.sub.3   H          H         u     s                                       CH.sub.3   CH.sub.2   H         s     s                                       CH.sub.3   CH.sub.3   --        s     u                                       CH.sub.2   CH.sub.3   H         s     s                                       CH.sub.3   CH.sub.3   H         u     s                                       CH.sub.2   H          OH        u     s                                       CH.sub.3   H          OH        s     s                                       ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 192S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

To a mixture of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(400 mg.) and methanol (10 ml.), an excess of sodium borohydride (100mg.) is added at 0° under nitrogen. The mixture is stirred for 2 hrs.and then treated with saturated ammonium chloride (20 ml.) and ether(100 ml.). The organic layer is dried and evaporated to give a brownoily reside which is chromatographed on a SilicAR column usingether-petroleum ether (1:1) as the eluting solvent. The major fractionis eluted to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(356 mg.):

I.R. (Neat) μ: 2.86 and 5.78;

N.M.R._(TMS) ^(CDCl).sbsp.3 δ: 5.3 (m, 2H, ═CH--CH₂ OAc, CH═C(CH₃)₂, 4.7(m, 3H, OCH₂, HC--OAc, 4.1 (bs, 2H, ═CH--CH₂ OAc), 3.45 (m, 1H, HCOH),2.03 (s, 6H, CH₃ --C═O).

EXAMPLE 202S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 2 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 212S,3R-3-Acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 6 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 222S,3R-3-Acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

A. A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane(422 mg.) in methylene chloride (80 ml.) is stirred with manganesedioxide (840 mg.) at room temperature under nitrogen for 17 hrs. Removalof the manganese dioxide by filtration followed by removal of thesolvent from the filtrate and washings in vacuo affords2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

B. Following the procedure of Example 11 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S,3R-6-[2-(tetrahydrofuran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl)-oxepan-3-ol,2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the method of Example 22B bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-ol.

    ______________________________________                                         ##STR23##                                                                      R.sub.4       R.sub.5                                                                              a         b   c                                        ______________________________________                                        CH.sub.3    H      u           u   s                                          H           H      s           s   s                                          CH.sub.3    H      s           s   s                                          H           --     s           s   u                                          H           H      u           s   s                                          CH.sub.3    H      s           u   s                                          CH.sub.3    H      u           s   s                                          H           H      u           u   s                                          CH.sub.2    H      u           s   s                                          CH.sub.3    --     u           s   u                                          H           H      s           u   s                                          CH.sub.2    H      s           s   s                                          CH.sub.3    --     s           s   u                                          H           OH     u           u   s                                          H           OH     s           s   s                                          H           OH     s           u   s                                          H           OH     u           s   s                                          ______________________________________                                         R.sub.1 -- OAc                                                                R.sub. 2 -- OAc                                                               R.sub.3 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 232S-6-(2-Oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

Following the procedure of Example 11 but substituting an equivalentamount of2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-onefor2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl)-oxepan-3-ol,2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oneis obtained.

The following compounds are prepared by the method of Example 23 bysubstituting an equivalent amount of the appropriate starting materialfor2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR24##                                                                      R.sub.4       R.sub.5                                                                              a         b   c                                        ______________________________________                                        CH.sub.3    H      u           u   s                                          H           H      s           s   s                                          CH.sub.3    H      s           s   s                                          H           --     s           s   u                                          H           H      u           s   s                                          CH.sub.3    H      s           u   s                                          CH.sub.3    H      u           s   s                                          H           H      u           u   s                                          CH.sub.2    H      u           s   s                                          CH.sub.3    --     u           s   u                                          H           H      s           u   s                                          CH.sub.2    H      s           s   s                                          CH.sub.3    --     s           s   u                                          H           OH     u           u   s                                          H           OH     s           s   s                                          H           OH     s           u   s                                          H           OH     u           s   s                                          ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- O                                                                  R.sub.3 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 242S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonyl)-oxepan-3-ol(Isomer A and B) ##STR25##

A mixture of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(821 mg.), platinum oxide (100 mg.), sodium nitrite (1.5 mg. in one dropof water) and absolute ethanol (100 ml.) is hydrogenated at atmosphericpressure for 1.3 hrs. The reaction mixture is filtered through celiteand the solvent is evaporated in vacuo. The residue is chromatographedon a SilicAR column using ethyl acetate:cyclohexane (2:3) as the elutingsolvent. The less polar fraction is eluted to afford Isomer A,2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonyl)-oxepan-3-ol(283 mg.):

I.R. (Neat) μ: 2.90 and 5.87;

N.M.R._(TMS) ^(CDCl).sbsp.3 δ: ##STR26## Further elution with ethylacetate-cyclohexane (1:1) affords Isomer B,2S,3R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonyl)-oxepan-3-ol(263 mg.):

I.R. (Neat) μ: 2.90 and 5.87;

N.M.R._(TMS) ^(CDCl).sbsp.3 δ: 0.9 [d, J=5 Hz, 6H, (CHHD 3)₂ --CH], 1.05(d, J=5 Hz, 3H, CHHD 3--C--H); 1.07 (s, 3H, CHHD 3--C--O), 2.42 (t, 2H,CHHD 2--C═O); 3.3 (d, J=7 Hz, 1H, >CHH); 3.5 (bs, 2H, --CHHD 2--O--R);3.7 (d, J=5 Hz, 2H, --CHHD 2OH).

EXAMPLE 252S,3R-6E-(2-Hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol##STR27##

The crude extract obtained by extracting the leaves of the zoapatleplant (50 g.) is dissolved in ether (5 l.) and the resulting solution isfiltered and washed with saturated sodium bicarbonate solution (500ml.). The ether is dried over anhydrous sodium sulfate, filtered andconcentrated to dryness to afford a light yellow oil (44.6 g.). This oilis then dissolved in chloroform (400 ml.) and the solution added to acolumn (4 in.×4 ft.) of 2.5 kg. of neutral silicic acid packed inchloroform. The column is eluted with chloroform, chloroform-isopropanolmixtures, and fractions are collected. The fractions are evaporated todryness in vacuo at a temperature below 40° C. The column is eluted asfollows:

    ______________________________________                                                 Volume/                                                                       Fraction                                                             Fraction (ml.)        Eluent                                                  ______________________________________                                         1-7     650          CHCl.sub.3                                               8-30    500          isopropanol:CHCl.sub.3 (1:41.7)                         31-60    500          isopropanol:CHCl.sub.3 (1:33.3)                         61-105   500          isopropanol:CHCl.sub.3 (1:28.6)                         ______________________________________                                    

The composition of the fractions is monitored by thin layerchromatography [silica gel, isopropanol-chloroform (1:12.5)] and by gaschromatography--3% OV17 [methyl silicone-phenyl silicone (1:1)] columnusing a programmed run (150°-250°). Fractions Nos. 78-84 are combinedand the solvent removed in vacuo to afford an oily residue (5.1 g.)which contains at least three components as indicated by gaschromatography.

A portion of the residue (3.2 g.) is then dissolved in benzene (50 ml.)and the solution added to a column (4 in.×35 in.) packed with 2 kg. ofOR-PVA Merck-O-Gel 2000 prepared in benzene. The column is eluted withbenzene and thin layer chromatography and gas chromatography are used tomonitor the composition of the fractions.

    ______________________________________                                                      Volume/                                                                       Fraction                                                               Fraction                                                                             (ml.)                                                           ______________________________________                                                1-7   1000                                                                    8-45   300                                                                   46-47  1000                                                            ______________________________________                                    

Fractions 23-33 contain 1.73 g. (54%) of the applied material.

Fractions 24-25 are evaporated to give2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-olas an oil (0.251 g.) having the following spectral characteristics:

I.R. (Neat) μ: 2.90, 5.96 and 6.21;

N.M.R. TMS^(CDCl).sbsp.3 δ: ##STR28## Mass Spec. [m/e]: 334 [M-18], 225,140, 111, 95, 81, 69;

U.V.-λ max (EtOH): ˜239 nm [ε=8500]

Chemical Ionization: M⁺ +H=353; M.W.=352

EXAMPLE 262S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol##STR29##

Following the hydrogenation procedure described in Example 24 butsubstituting an equivalent amount of2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-olfor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,a mixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-olis obtained.

EXAMPLE 272S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane

A solution of m-chloroperoxybenzoic acid (85%, 80 mg.) in methylenechloride (2 ml.) is slowly added to a cooled (0°-5°) solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(139 mg.) in methylene chloride (2 ml.). The reaction mixture is stirredat 0°-5° for 1 hr. and then at room temperature for 2 hrs. The mixtureis treated with 5% aqueous sodium bisulfite solution, and the organiclayer is washed with 5% aqueous sodium bicarbonate solution (2×25 ml.),and brine (2×25 ml.). The mixture is dried, concentrated in vacuo andpurified by preparative thin layer chromatography to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane.

EXAMPLE 282S,3R-3-Acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane##STR30##

A mixture of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane.(438 mg.), platinum oxide (50 mg.), and sodium nitrite (0.5 mg. in onedrop of water) in absolute ethanol (50 ml.) is hydrogenated atatmospheric pressure until one molar equivalent of hydrogen is taken up.The catalyst is removed by filtration and the filtrate evaporated invacuo to afford a mixture of isomers of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane.

EXAMPLE 292S,3R-3-Acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane##STR31##

A solution of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane(440 mg.) in absolute ethanol (200 ml.) containing zinc-copper couple(10 g.) is refluxed for 48 hrs. Removal of the metal by filtrationfollowed by evaporation of the solvent in vacuo affords a mixture ofisomers of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

EXAMPLE 302S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol##STR32##

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(426 mg.) in methanol (100 ml.) is stirred at room temperature undernitrogen with potassium carbonate (332 mg.) in water (30 ml.) for 19hrs. The mixture is evaporated in vacuo, and the residue extracted withmethylene chloride. The extracts are dried and evaporated to afford amixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

EXAMPLE 312S,3R-6-[2'-Hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol

To a stirred solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(338 mg.) and vanadyl acetylacetonate (10 mg.) in benzene (10 ml.) atroom temperature is added dropwise over a period of 10 mins.t-butylhydroperoxide (˜94%, 152 mg.). After six hrs., the resultingsolution is washed with 10% aqueous sodium bisulfite solution, water anddried. Removal of the solvent, in vacuo, and purification of the residueby chromatography affords2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

EXAMPLE 322S,3R-6-[2'-Hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxononyl)-oxepan-3-ol

Following the hydrogenation procedure of Example 28 but substituting anequivalent amount of2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane,there is obtained2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxononyl)-oxepan-3-ol.

EXAMPLE 332S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-oxepan-3-ol

Following the procedure of Example 29 but substituting an equivalentamount of2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxononyl)-oxepan-3-olfor2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane,there is obtained2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-oxepan-3-ol.

EXAMPLE 342S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol(352 mg.) in methanol (10 ml.) is treated with 30% aqueous hydrogenperoxide (0.5 ml.) and 6N aqueous sodium hydroxide (1 ml.). Theresulting mixture is stirred for 3 hrs. at room temperature and thentreated with water (50 ml.) and ether (100 ml.). The organic layer isdried and evaporated to give2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol.

EXAMPLE 352S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol##STR33##

A mixture of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol(368 mg.), platinum oxide (30 mg.), sodium nitrite (1 mg.) and absoluteethanol (50 ml.) is hydrogenated at atmospheric pressure for 1.5 hr. Theresulting mixture is filtered through celite and the solvent isevaporated to give a mixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol.

EXAMPLE 362S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-oxepan-3-ol##STR34##

Following the procedure of Example 29 but substituting an equivalentamount of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-olfor2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane,a mixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 372S,3R-6-[2'-Hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-oxepan-3-ol

Following the procedure of Example 31 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 382S,3R-6-[2'-Hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol

Following the procedure of Example 32 but substituting an equivalentamount of2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-oxepan-3-olfor2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-olis obtained.

EXAMPLE 392S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol

Following the procedure of Example 33 but substituting an equivalentamount of2S-3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-olfor2S,3R-6-[2'-hydroxy-(6,1'-oxido)-ethyl]-2-methyl-2-(4,8-dimethyl-5-oxononyl)-oxepan-3-ol,2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-oxepan-3-olis obtained.

EXAMPLE 402S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-oxepan-3-ol

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(338 mg.) in anhydrous ethanol (5 ml.) is treated with sodium (230 mg.)in ethanol (10 ml.) and the resulting solution is allowed to stand for14 hours. The solution is then diluted with cold water and quicklyextracted with ether. The organic layer is washed with saturated saltsolution, dried and evaporated to give2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-oxepan-3-ol.

EXAMPLES 41 AND 422S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepan-3-ol

and

2S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepan-3-ol

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol(352 mg.) in t-butanol (5 ml.) is treated with a solution of potassiumt-butoxide (1.12 g.) in t-butanol (50 ml.). The resulting solution isstirred at 25° for 16 hrs., then poured into 10% acetic acid (50 ml.).The reaction mixture is then treated with dilute sodium bicarbonatesolution and extracted with ether. The ether extract is washed withsaturated salt solution, dried and evaporated to give a mixture of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepan-3-oland2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepan-3-ol,which are separated by chromatography.

EXAMPLE 432S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-6,7-oxido-5-oxononyl)-oxepan-3-ol

Following the procedure of Example 34 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol,2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-6,7-oxido-5-oxononyl)-oxepan-3-olis obtained.

EXAMPLE 442S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-6,7-oxido-5-oxononyl)-oxepan-3-ol##STR35##

Following the procedure of Example 35 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-6,7-oxido-5-oxononyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol,a mixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-6,7-oxido-5-oxononyl)-oxepan-3-olis obtained.

EXAMPLE 452S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-oxepan-3-ol##STR36##

Following the procedure of Example 36 but substituting an equivalentamount of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-6,7-oxido-5-oxononyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethyl)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol,an isomeric mixture of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 462S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepane

Following the procedure of Example 2 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepaneis obtained.

EXAMPLE 472S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,1'-oxidomethylene-5-oxononyl)-oxepane

Following the procedure of Example 27 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,1'-oxidomethylene-5-oxononyl)-oxepaneis obtained.

EXAMPLE 482S,3R-3-Acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,1'-oxidomethylene-5-oxononyl-oxepane##STR37##

Following the procedure of Example 28 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,1'-oxidomethylene-5-oxononyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane,a mixture of isomers of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,1'-oxidomethylene-5-oxononyl)-oxepaneis obtained.

EXAMPLE 492S,3R-3-Acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepane##STR38##

Following the procedure of Example 29 but substituting an equivalentamount of the isomeric mixture of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,1'-oxidomethylene-5-oxononyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane,a mixture of isomers of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepaneis obtained.

EXAMPLE 502S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepan-3-ol##STR39##

Following the procedure of Example 30 but substituting an equivalentamount of the isomeric mixture of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepanefor2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,a mixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-oxepan-3-olis obtained.

EXAMPLE 512S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 2 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepan-3-olfor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 522S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(7,8-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepane

Following the procedure of Example 27 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-(7,8-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepaneis obtained.

EXAMPLE 532S,3R-3-Acetoxy-6ξ-(2-actoxyethyl)-2-methyl-2-(7,8-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepane##STR40##

Following the procedure of Example 28 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(7,8-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepanea mixture of isomers of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(7,8-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepaneis obtained.

EXAMPLE 542S,3R-3-Acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepane##STR41##

Following the procedure of Example 29 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(7,oxido-5-oxo-4,7,8-trimethylnonyl)-oxepane(53a, 53b) for2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxononyl)-oxepane,a mixture of isomers of2S,3R-3-acetoxy-6ξ-(2-acetoxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 552S,3R-6ξ-(2-Hydroxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepan-3-ol##STR42##

Following the procedure of Example 30 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,a mixture of isomers of2S,3R-6ξ-(2-hydroxyethyl)-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 562S-2-Methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-on

A solution of2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(334 mg) in tetrahydrofuran:water (9:1) (10 ml.) is treated withargentic oxide (460 mg.) with vigorous stirring. Afrer 14 hrs. thesuspension is filtered, and the filtrate is evaporated to dryness. Theresidue is treated with dilute sodium bicarbonate solution and extractedwith ether. The aqueous layer is acidified to pH 3 with dilutehydrochloric acid and extracted with ether. The ether extracts are driedand evaporated to give2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

The following compounds are prepared by the method of Example 56 bysubstituting an equivalent amount of the appropriate starting materialfor2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR43##                                                                      R.sub.4       R.sub.5                                                                              a         b   c                                        ______________________________________                                        CH.sub.3    H      u           u   s                                          H           H      s           s   s                                          CH.sub.3    H      s           s   s                                          H           --     s           s   u                                          H           H      u           s   s                                          CH.sub.3    H      s           u   s                                          CH.sub.3    H      u           s   s                                          H           H      u           u   s                                          CH.sub.2    H      u           s   s                                          CH.sub.3    --     u           s   u                                          H           H      s           u   s                                          CH.sub.2    H      s           s   s                                          CH.sub.3    --     s           s   u                                          H           OH     u           u   s                                          H           OH     s           s   s                                          H           OH     s           u   s                                          H           OH     u           s   s                                          ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2  -- O                                                                 R.sub.3 -- COOH                                                               u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 572S,3R-3-Acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Following the procedure of Example 56 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-6-oxo-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the method of Example 57 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR44##                                                                      R.sub.4       R.sub.5                                                                              a         b   c                                        ______________________________________                                        CH.sub.3    H      u           u   s                                          H           H      s           s   s                                          CH.sub.3    H      s           s   s                                          H           --     s           s   u                                          H           H      u           s   s                                          CH.sub.3    H      s           u   s                                          CH.sub.3    H      u           s   s                                          H           H      u           u   s                                          CH.sub.2    H      u           s   s                                          CH.sub.3    --     u           s   u                                          H           H      s           u   s                                          CH.sub.2    H      s           s   s                                          CH.sub.3    --     s           s   u                                          H           OH     u           u   s                                          H           OH     s           s   s                                          H           OH     s           u   s                                          H           OH     u           s   s                                          ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2  -- OAc                                                               R.sub.3 -- COOH                                                               u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 582S-2-Methyl-6-carboxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one

Following the procedure of Example 56 but substituting an equivalentamount of2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-onefor2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-oneis obtained.

The following compounds are prepared by the method of Example 58 bysubstituting an equivalent amount of the appropriate starting materialfor2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR45##                                                                      R.sub.4       R.sub.5                                                                              a         b   c                                        ______________________________________                                        CH.sub.3    H      u           u   s                                          H           H      s           s   s                                          CH.sub.3    H      s           s   s                                          H           --     s           s   u                                          H           H      u           s   s                                          CH.sub.3    H      s           u   s                                          CH.sub.3    H      u           s   s                                          H           H      u           u   s                                          CH.sub.2    H      u           s   s                                          CH.sub.3    --     u           s   u                                          H           H      s           u   s                                          CH.sub.2    H      s           s   s                                          CH.sub.3    --     s           s   u                                          ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- O                                                                  R.sub.3 -- COOH                                                               u -- unsaturated                                                              s --  saturated                                                          

EXAMPLE 592S,3R-3-Acetoxy-2-methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 56 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the method of Example 59 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR46##                                                                      R.sub.4       R.sub.5                                                                              a         b   c                                        ______________________________________                                        CH.sub.3    H      u           u   s                                          H           H      s           s   s                                          CH.sub.3    H      s           s   s                                          H           --     s           s   u                                          H           H      u           s   s                                          CH.sub.3    H      s           u   s                                          CH.sub.3    H      u           s   s                                          H           H      u           u   s                                          CH.sub.2    H      u           s   s                                          CH.sub.3    --     u           s   u                                          H           H      s           u   s                                          CH.sub.2    H      s           s   s                                          CH.sub.3    --     s           s   u                                          H           OH     u           u   s                                          H           OH     s           s   s                                          H           OH     s           u   s                                          H           OH     u           s   s                                          ______________________________________                                         R.sub.1 -- OAc                                                                R.sub.2  -- OAc                                                               R.sub.3 -- COOH                                                               u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 602S-2-Methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

Method A. An excess of diazomethane is added at 0° to a mixture of2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(350 mg.) and ether (20 ml.). The resulting mixture is treated withglacial acetic acid (10 ml.) and then washed with 10% aqueous sodiumbicarbonate solution. The organic layer is dried and evaporated to give2S-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

Method B. A mixture of2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(350 mg.), methanol (10 ml.) and concentrated sulfuric acid (0.1 ml.) isrefluxed for 5 hrs. under nitrogen, then treated with water (50 ml) at0°. Most of the methanol is removed in vacuo and the residue isextracted with ether. The organic layer is dried and evaporated to give2S-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

The following compounds are prepared by the methods of Example 60 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

Similarly, by substituting an appropriate alcohol for methanol in theprocedure of Example 60, (Method B), the corresponding esters areformed. Thus, for example, ethanol, propanol, t-butanol and benzylalcohol afford the ethyl, propyl, t-butyl and benzyl estersrespectively.

    ______________________________________                                         ##STR47##                                                                      R.sub.4    R.sub.5                                                                              R.sub.6                                                                              a   b     c   Method                               ______________________________________                                        CH.sub.3 H      CH.sub.3 u   u     s   A                                      H        H      C.sub.2 H.sub.5                                                                        s   s     s   B                                      CH.sub.3 H      C.sub.4 H.sub.9                                                                        s   s     s   B                                      H        --     C.sub.3 H.sub.7                                                                        s   s     u   B                                      H        H      CH.sub.3 u   s     s   A                                      CH.sub.3 H      C.sub.2 H.sub.5                                                                        s   u     s   B                                      CH.sub.3 H      CH.sub.3 u   s     s   A                                      H        H      CH.sub.3 u   u     s   A                                      CH.sub.2 H      CH.sub.3 u   s     s   A                                      CH.sub.3 --     CH.sub.3 u   s     u   A                                      H        H      C.sub.3 H.sub. 7                                                                       s   u     s   B                                      CH.sub.2 H      C.sub.2 H.sub.5                                                                        s   s     s   B                                      CH.sub.3 --     C.sub.3 H.sub.7                                                                        s   s     u   B                                      H        OH     CH.sub.3 u   u     s   A                                      H        OH     C.sub.3 H.sub.7                                                                        s   s     s   B                                      H        OH     C.sub.2 H.sub.5                                                                        s   u     s   B                                      H        OH     C.sub.3 H.sub.7                                                                        u   s     s   B                                      ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- O                                                                  R.sub.3 -- COOR.sub.6                                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the methods of Example 60 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR48##                                                                      R.sub.3   R.sub.4 R.sub.5    b   c     Method                               ______________________________________                                        CH.sub.3                                                                              H       CH.sub.3     u   s     A                                      H       H       C.sub.4 H.sub.9                                                                            s   s     B                                      CH.sub.3                                                                              H       CH.sub.3     s   s     A                                      H       H       CH.sub.2C.sub.6 H.sub.5                                                                    u   s     B                                      CH.sub.2                                                                              H       C.sub.6 H.sub.5                                                                            s   s     B                                      CH.sub.3                                                                              --      C.sub.2 H.sub.5                                                                            s   u     B                                      H       OH      CH.sub.3     u   s     A                                      H       OH      CH.sub.3     s   s     A                                      ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- COOR.sub.5                                                         5 -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the methods of Example 60 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-carboxy-methylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR49##                                                                        R.sub.3 R.sub.4   R.sub.5                                                                            b      c   Method                                  ______________________________________                                        CH.sub.3                                                                              H         CH.sub.3                                                                             u      s   A                                         H       H         C.sub.2 H.sub.5                                                                      s      s   B                                         CH.sub.3                                                                              H         C.sub.4 H.sub.9                                                                      s      s   B                                         H       H         C.sub.3 H.sub.7                                                                      u      s   B                                         CH.sub.2                                                                              H         C.sub.3 H.sub.7                                                                      s      s   B                                         CH.sub.3                                                                              --        C.sub.2 H.sub.5                                                                      s      u   B                                         H       OH        CH.sub.3                                                                             u      s   A                                         H       OH        CH.sub.3                                                                             s      s   A                                         ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- COOR.sub.5                                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 612S,3R-3-Acetoxy-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Following the procedures of Example 60 but substituting an equivalentamount of2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-3-acetoxy-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the methods of Example 61 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

Similarly, by substituting an appropriate alcohol for methanol in theprocedure of Example 61, (Method B), the corresponding esters areformed. Thus, for example, ethanol, propanol, t-butanol and benzylalcohol afford the ethyl, propyl, t-butyl and benzyl estersrespectively.

    ______________________________________                                         ##STR50##                                                                      R.sub.4 R.sub.5 R.sub.6   a     b   c     Method                            ______________________________________                                        CH.sub.3                                                                            H       CH.sub.3    u     u   s     A                                   H     H       C.sub.4 H.sub.9                                                                           s     s   s     B                                   CH.sub.3                                                                            H       C.sub.2 H.sub.5                                                                           s     s   s     B                                   H     --      CH.sub.2C.sub.6 H.sub.5                                                                   s     s   u     B                                   H     H       CH.sub.3    u     s   s     A                                   CH.sub.3                                                                            H       C.sub.3 H.sub.7                                                                           s     u   s     B                                   CH.sub.3                                                                            H       CH.sub.3    u     s   s     A                                   H     H       CH.sub.3    u     u   s     A                                   CH.sub.2                                                                            H       CH.sub.3    u     s   s     A                                   CH.sub.3                                                                            --      CH.sub.3    u     s   u     A                                   H     H       C.sub.3 H.sub.7                                                                           s     u   s     B                                   CH.sub.2                                                                            H       C.sub.2 H.sub.5                                                                           s     s   s     B                                   CH.sub.3                                                                            --      C.sub.4 H.sub.9                                                                           s     s   u     B                                   H     OH      CH.sub.3    u     u   s     A                                   H     OH      C.sub.2 H.sub.5                                                                           s     s   s     B                                   H     OH      C.sub.3 H.sub.7                                                                           s     u   s     B                                   H     OH      C.sub.4 H.sub.9                                                                           u     s   s     B                                   ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- OAc                                                                R.sub.3 -- COOR.sub.6                                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 622S-2-Methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one

Following the procedures of Example 60 but substituting an equivalentamount of2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-onefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-oneis obtained.

The following compounds are prepared by the methods of Example 62 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

Similarly, by substituting an appropriate alcohol for methanol in theprocedure of Example 62, (Method B), the corresponding esters areformed. Thus, for example, ethanol, propanol, t-butanol and benzylalcohol afford the ethyl, propyl, t-butyl and benzyl estersrespectively.

    ______________________________________                                         ##STR51##                                                                      R.sub.4 R.sub.5 R.sub.6   a     b   c     Method                            ______________________________________                                        CH.sub.3                                                                            H       CH.sub.3    u     u   s     A                                   H     H       CH.sub.2C.sub.6 H.sub.5                                                                   s     s   s     B                                   CH.sub.3                                                                            H       C.sub.3 H.sub.7                                                                           s     s   s     B                                   H     --      C.sub.4 H.sub.9                                                                           s     s   u     B                                   H     H       CH.sub.3    u     s   s     A                                   CH.sub.3                                                                            H       C.sub.2 H.sub.5                                                                           s     u   s     B                                   CH.sub.3                                                                            H       CH.sub.3    u     s   s     A                                   H     H       CH.sub.3    u     u   s     A                                   CH.sub.2                                                                            H       CH.sub.3    u     s   s     A                                   CH.sub.3                                                                            --      CH.sub.3    u     s   u     A                                   H     H       C.sub.3 H.sub.7                                                                           s     u   s     B                                   CH.sub.2                                                                            H       C.sub.2 H.sub.5                                                                           s     s   s     B                                   CH.sub.3                                                                            --      CH.sub.3    s     s   u     B                                   ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- O                                                                  R.sub.3 -- COOR.sub.6                                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 632S,3R-3-Acetoxy-2-methyl-6-carbmethoxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 60 but substituting an equivalentamount of2S,3R-acetoxy-2-methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oneaffords2S,3R-3-acetoxy-2-methyl-6-carbmethoxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

Similarly, by substituting an appropriate alcohol for methanol in theprocedure of Example 63 (Method B), the corresponding esters are formed.Thus, for example, ethanol, propanol, t-butanol and benzyl alcoholafford the ethyl, propyl, t-butyl and benzyl esters respectively.

The following compounds are prepared by the method of Example 63 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR52##                                                                      R.sub.4 R.sub.5 R.sub.6   a     b   c     Method                            ______________________________________                                        CH.sub.3                                                                            H       CH.sub.3    u     u   s     A                                   H     H       C.sub.2 H.sub.5                                                                           s     s   s     B                                   CH.sub.3                                                                            H       C.sub.3 H.sub.7                                                                           s     s   s     B                                   H     --      C.sub.3 H.sub.7                                                                           s     s   u     B                                   H     H       CH.sub.3    u     s   s     A                                   CH.sub.3                                                                            H       C.sub.4 H.sub.9                                                                           s     u   s     B                                   CH.sub.3                                                                            H       CH.sub.3    u     s   s     A                                   H     H       CH.sub.3    u     u   s     A                                   CH.sub.2                                                                            H       CH.sub.3    u     s   s     A                                   CH.sub.3                                                                            --      CH.sub.3    u     s   u     A                                   H     H       CH.sub. 2C.sub.6 H.sub.5                                                                  s     u   s     B                                   CH.sub.2                                                                            H       C.sub.2 H.sub.5                                                                           s     s   s     B                                   CH.sub.3                                                                            --      CH.sub.3    s     s   u     B                                   H     OH      CH.sub.3    u     u   s     A                                   H     OH      C.sub.3 H.sub.7                                                                           s     s   s     B                                   H     OH      C.sub.2 H.sub.5                                                                           s     u   s     B                                   H     OH      C.sub.4 H.sub.9                                                                           u     s   s     B                                   ______________________________________                                         R.sub.1 -- OAc                                                                R.sub.2 -- OAc                                                                R.sub.3 -- COOR.sub.6                                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 642S-2-Methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,sodium salt

A solution of2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(350 mg.) in 1:1 tetrahydrofuran:water (10 ml.) is titrated with anequivalent amount of 1N sodium hydroxide solution. The resultingsolution is evaporated to afford2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,sodium salt.

Similarly, by substituting other basic hydroxides for sodium hydroxidein the procedure of Example 64, the corresponding salts are formed.Thus, for example, potassium hydroxide and ammonium hydroxide afford thepotassium and ammonium salts respectively.

The following compounds are prepared by the method of Example 64 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR53##                                                                        R.sub.4 R.sub.5    R.sub.6                                                                             a       b  c                                     ______________________________________                                        CH.sub.3                                                                              H          Na      u       u   s                                      H       H          K       s       s   s                                      CH.sub.3                                                                              H          Li      s       s   s                                      H       --         Na      s       s   u                                      H       H          (1/2 Ca)                                                                              u       s   s                                      CH.sub.3                                                                              H          K       s       u   s                                      CH.sub.3                                                                              H          (1/2 Mg)                                                                              u       s   s                                      H       H          Na      u       u   s                                      CH.sub.2                                                                              H          Li      u       s   s                                      CH.sub.3                                                                              --         Na      u       s   u                                      H       H          Na      s       u   s                                      CH.sub.2                                                                              H          NH.sub.4                                                                              s       s   s                                      CH.sub.3                                                                              --         Na      s       s   u                                      H       OH         NH.sub.4                                                                              u       u   s                                      H       OH         Li      s       s   s                                      H       OH         (1/2 Ca)                                                                              s       u   s                                      H       OH         Na      u       s   s                                      ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- O                                                                  R.sub.3 -- COOR.sub.6                                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 652S,3R-3-Acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of oxalyl chloride (1.65 ml.) in dry benzene (5 ml.) isslowly added to a stirred solution of2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(394 mg.) in dry benzene (15 ml.) at 0°, and the mixture stirred at 0°for 1 hr. The solvent and excess of oxalyl chloride are removed in vacuoto afford2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

EXAMPLE 662S,3R-3-Acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

To a well chilled (-30°) and stirred solution of anhydrous ammonia (34mg.) in dry methylene chloride (25 ml.) is slowly added a solution offreshly prepared2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(413 mg.) in dry methylene chloride (25 ml.) over a period of 3 hrs.while maintaining the reaction temperature below 0°. The solvent isevaporated in vacuo to afford2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

Similarly, by substituting appropriate amines for ammonia in theprocedure of Example 66, the corresponding amides are prepared. Thus,for example, dimethylamine, ethylamine, benzylamine and diphenylamineafford the dimethylamide, ethylamide, benzylamide and diphenylamiderespectively.

Similarly, by substituting hydrazines and substituted hydrazides forammonia in the procedure of Example 66, the corresponding acylhydrazidesare formed. Thus, for example, hydrazine, dimethylhydrazine,phenylhydrazine and p-toluenesulfonylhydrazide afford the correspondinghydrazide, dimethylhydrazide, phenylhydrazide andp-toluenesulfonylhydrazides respectively.

The following compounds are prepared by the method of Example 66 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand the appropriate amino compound.

    ______________________________________                                         ##STR54##                                                                      R.sub.4 R.sub.5                                                                              R.sub.6    R.sub.7  a    b    c                              ______________________________________                                        CH.sub.3                                                                            H      C.sub.2 H.sub.5                                                                            H        u    u    s                                H     H      H            H        s    s    s                                CH.sub.3                                                                            H      CH.sub.2C.sub.6 H.sub.5                                                                    H        s    s    s                                H     --     CH.sub.3     CH.sub.3 s    s    u                                H     H      C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                                                        u    s    s                                CH.sub.3                                                                            H      C.sub.6 H.sub.5                                                                            C.sub.6 H.sub.5                                                                        s    u    s                                CH.sub.3                                                                            H      H            H        u    s    s                                H     H      CH.sub.3     H        u    u    s                                CH.sub.2                                                                            H      C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                                                        u    s    s                                CH.sub. 3                                                                           --     C.sub.4 H.sub.9                                                                            H        u    s    u                                H     H      CH.sub.3     CH.sub.3 s    u    s                                CH.sub.2                                                                            H      H            C.sub.2 H.sub.5                                                                        s    s    s                                CH.sub.3                                                                            --     H            CH.sub.3 s    s    u                                H     H      H            NH.sub.2 s    s    s                                CH.sub.3                                                                            H      H            N(CH.sub.3).sub.2                                                                      u    u    s                                CH.sub.3                                                                            H      H            NHC.sub.6 H.sub.5                                                                      u    u    s                                ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- OAc                                                                ##STR55##                                                                     u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 672S,3R-3-Acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

To a solution of2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(381 mg.) in ethanol (20 ml.) at 0° is slowly added sodium borohydride(40 mg.) and the mixture stirred at 0° for 5 minutes. The mixture isthen quickly treated with saturated aqueous ammonium chloride solutionand extracted with chloroform. The chloroform extract is washed withbrine, dried and evaporated to dryness in vacuo to afford2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane.

Similarly, by substituting appropriate keto amides for2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanein the procedure of Example 67, the corresponding hydroxy amides areformed. Thus, for example, the dimethylamide and ethylamide of Example66 afford the corresponding hydroxyamides.

The following compounds are prepared by the method of Example 67 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR56##                                                                      R.sub.4   R.sub.5                                                                             R.sub.6     R.sub.7                                                                            a     b   c                                ______________________________________                                        CH.sub.3                                                                              H     C.sub.2 H.sub.5                                                                             H    u     u   s                                  H       H     H             H    s     s   s                                  CH.sub.3                                                                              H     CH.sub.2C.sub.6 H.sub.5                                                                     H    s     s   s                                  H       --    CH.sub.3      CH.sub.3                                                                           s     s   u                                  H       H     C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                    u     s   s                                  CH.sub.3                                                                              H     C.sub.6 H.sub.5                                                                             C.sub.6 H.sub.5                                                                    s     u   s                                  CH.sub.3                                                                              H     H             H    u     s   s                                  H       H     CH.sub.3      H    u     u   s                                  CH.sub.2                                                                              H     C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                    u     s   s                                  CH.sub.3                                                                              --    C.sub.4 H.sub.9                                                                             H    u     s   u                                  H       H     CH.sub.3      CH.sub.3                                                                           s     u   s                                  CH.sub.2                                                                              H     H             C.sub.2 H.sub.5                                                                    s     s   s                                  CH.sub.3                                                                              --    H             CH.sub.3                                                                           s     s   u                                  ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- OAc                                                                ##STR57##                                                                     u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 682S-2-Methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 2 but substituting an equivalentamount of2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-onefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S-2-methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one.

EXAMPLE 692S-2-Methyl-6-chloroformylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 65 but substituting an equivalentamount of2S-2-methyl-6-carboxymethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S-2-methyl-6-chloroformylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one.

EXAMPLE 702S-2-Methyl-6-carbamoylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 66 but substituting an equivalentamount of2S-2-methyl-6-chloroformylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S-2-methyl-6-carbamoylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one.

Similarly by substituting appropriate amines for ammonia in theprocedure of Example 70, the corresponding amides are formed. Thus, forexample, diethylamine, methylamine and diphenylamine afford thediethylamide, methylamide and diphenylamide respectively.

EXAMPLE 712S-2-Methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one

Following the procedure of Example 10 but substituting an equivalentamount of2S-2-methyl-6-carbamoylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-3-acetoxy-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane,there is obtained2S-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one.

Similarly, by substituting appropriate N-substituted acetoxy amides fromExample 70 for2S-2-methyl-6-carbamoylmethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onein the procedure of Example 71, the corresponding hydroxy amides areobtained.

The following compounds are prepared by the method of Example 71 bysubstituting an equivalent amount of the appropriate starting materialfor 2S-2-methyl-6-carbamoylmethylene2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR58##                                                                      R.sub.4   R.sub.5                                                                             R.sub.6     R.sub.7                                                                            a     b   c                                ______________________________________                                        CH.sub.3                                                                              H     C.sub.2 H.sub.5                                                                             H    u     u   s                                  H       H     H             H    s     s   s                                  CH.sub.3                                                                              H     CH.sub.2C.sub.6 H.sub.5                                                                     H    s     s   s                                  H       --    CH.sub.3      CH.sub.3                                                                           s     s   u                                  H       H     C.sub.2 H.sub.5                                                                             C.sub.2 H.sub.5                                                                    u     s   s                                  CH.sub.3                                                                              H     C.sub.6 H.sub.5                                                                             C.sub.6 H.sub.5                                                                    s     u   s                                  CH.sub.3                                                                              H     H             H    u     s   s                                  H       H     CH.sub.3      H    u     u   s                                  CH.sub.2                                                                              H     C.sub.2 H.sub.5                                                                             C.sub.2 H.sub. 5                                                                   u     s   s                                  CH.sub.3                                                                              --    C.sub.4 H.sub.9                                                                             H    u     s   u                                  H       H     CH.sub.3      CH.sub.3                                                                           s     u   s                                  CH.sub.2                                                                              H     H             C.sub.2 H.sub.5                                                                    s     s   s                                  CH.sub.3                                                                              --    H             CH.sub.3                                                                           s     s   u                                  ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- O                                                                  ##STR59##                                                                                                                                                   u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 722S-2-Methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

Following the procedure of Example 65 but substituting an equivalentamount of2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)oxepan-3-onefor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

EXAMPLE 732S-2-Methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

Following the procedure of Example 66 but substituting an equivalentamount of2S-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-onefor2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

Similarly, by substituting appropriate amines for ammonia in theprocedure of Example 73, the corresponding amides are formed. Thus, forexample, butylamine, dipropylamine and dibenzylamine afford thebutylamine, dipropylamide and dibenzylamide respectively.

The following compounds are prepared by the method of Example 73 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-chloroformyl-methylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR60##                                                                      R.sub.4 R.sub.5                                                                              R.sub.6   R.sub.7   a    b   c                               ______________________________________                                        CH.sub.3                                                                            H      H           H         u    u   s                                 H     H      CH.sub.3    CH.sub.3  s    s   s                                 CH.sub.3                                                                            H      CH.sub.3    H         s    s   s                                 H     --     H           CH.sub.2C.sub.6 H.sub.5                                                                 s    s   u                                 H     H      CH.sub.2C.sub.6 H.sub.5                                                                   CH.sub.2C.sub.6 H.sub.5                                                                 u    s   s                                 CH.sub.3                                                                            H      C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                         s    u   s                                 CH.sub.3                                                                            H      C.sub.3 H.sub.7                                                                           H         u    s   s                                 H     H      H           H         u    u   s                                 CH.sub.2                                                                            H      CH.sub. 3   CH.sub.3  u    s   s                                 CH.sub.3                                                                            --     CH.sub.3    CH.sub.2C.sub.6 H.sub.5                                                                 u    s   u                                 H     H      C.sub.6 H.sub.5                                                                           C.sub.2 H.sub.5                                                                         s    u   s                                 CH.sub.2                                                                            H      CH.sub.3    H         s    s   s                                 CH.sub.3                                                                            --     H           H         s    s   u                                 ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- O                                                                  ##STR61##                                                                                                                                                   u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 742S-3,3-Dimethoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane

A solution of2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(336 mg.) in absolute methanol (2 ml.) and trimethyl orthoformate (1ml.) is treated with one drop of 4.4N methylsulfuric acid. Afterstirring for 24 hrs. at room temperature, the solution is made basicwith cold 5% sodium hydroxide in methanol, diluted with cold water andextracted with ether. The ether extract is washed with water, dried andevaporated to give2S-3,3-dimethoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 752S-3,3-Dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 11, but substituting an equivalentamount of2S-3,3-dimethoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-olaffords2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 762S-3,3-Dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane

A solution of2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane(426 mg.) in anhydrous pyridine (5 ml.) is treated with a solution ofhydroxylamine hydrochloride (200 mg.) in pyridine (2 ml.). Afterstanding at 25° C. for 24 hrs., the pyridine is evaporated and theresidue is partitioned between ether and water. The aqueous layer isfurther extracted with ether and the combined organic extract is driedand evaporated to give2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 772S-3,3-Dimethoxy-2-methyl-6-cyanomethylene-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane

A solution of2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane(441 mg.) in acetic anhydride (1 ml.) is treated with anhydrous sodiumacetate (3 mg.) at reflux for 5 hrs. The reaction mixture is poured intocold water (10 ml.) and extracted with ether. The combined etherextracts are dried and evaporated to give2S-3,3-dimethoxy-2-methyl-6-cyanomethylene-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 782S-2-Methyl-6-cyanomethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

A solution of2S-3,3-dimethoxy-2-methyl-6-cyano-methylene-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane(423 mg.) in a 2:1 mixture of chloroform:5% aqueous trifluoroacetic acid(30 ml.) is stirred at 25° C. for 2 hrs. The organic and aqueous phasesare separated, the aqueous phase is extracted with additionalchloroform, and the organic extracts are combined, dried and evaporatedto give2S-2-methyl-6-cyanomethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one

The following compounds are prepared by the method of Example 78 bysubstituting an equivalent amount of the appropriate starting materialfor2S-3,3-dimethoxy-2-methyl-6-cyanomethylene-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR62##                                                                      R.sub.4       R.sub.5                                                                             a          b    c                                       ______________________________________                                        CH.sub.3    H     u            u    s                                         H           H     s            s    s                                         CH.sub.3    H     s            s    s                                         H           --    s            s    u                                         H           H     u            s    s                                         CH.sub.3    H     s            u    s                                         CH.sub.3    H     u            s    s                                         H           H     u            u    s                                         CH.sub.2    H     u            s    s                                         CH.sub.3    --    u            s    u                                         H           H     s            u    s                                         CH.sub.2    H     s            s    s                                         CH.sub.3    --    s            s    u                                         ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- O                                                                  R.sub.3 -- C N                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 792S,3R-3-Acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 76, but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 802S,3R-3-Acetoxy-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 77, but substituting an equivalentamount of2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3R-3-acetoxy-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the method of Example 80 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR63##                                                                      EXAMPLE    R.sub.4     R.sub.5                                                                           a       b   c                                    ______________________________________                                               CH.sub.3  H     u         u   s                                               H         H     s         s   s                                               CH.sub.3  H     s         s   s                                               H         --    s         s   u                                               H         H     u         s   s                                               CH.sub.3  H     s         u   s                                               CH.sub.3  H     u         s   s                                               H         H     u         u   s                                               CH.sub.2  H     u         s   s                                               CH.sub.3  --    u         s   u                                               H         H     s         u   s                                               CH.sub.2  H     s         s   s                                               CH.sub.3  --    s         s   u                                        ______________________________________                                         R.sub.1 -- OAc                                                                R.sub.2 -- OAc                                                                R.sub.3 -- C N                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 812S-3,3-Dimethoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 74, but substituting an equivalentamount of2S-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S-3,3-dimethoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 822S-3,3-Dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 11, but substituting an equivalentamount of2S-3,3-dimethoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-ol,2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 832S-3,3-Dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 76, but substituting an equivalentamount of2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 842S-3,3-Dimethoxy-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 77, but substituting an equivalentamount of2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S-3,3-dimethoxy-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneis obtained.

EXAMPLE 852S-2-Methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 78, but substituting an equivalentamount of2S-3,3-dimethoxy-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-2-methyl-6-cyanomethylene-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-oneis obtained.

EXAMPLE 862S-2-Methyl-6-cyanomethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

Following the procedure of Example 10, but substituting an equivalentamount of2S-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-3-acetoxy-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepane,2S-2-methyl-6-cyanomethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the method of Example 86 bysubstituting an equivalent amount of the appropriate starting materialfor2S-2-methyl-6-cyanomethylene-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one.

    ______________________________________                                         ##STR64##                                                                      R.sub.4       R.sub.5                                                                             a          b   c                                        ______________________________________                                        CH.sub.3    H     u            u   s                                          H           H     s            s   s                                          CH.sub.3    H     s            s   s                                          H           --    s            s   u                                          H           H     u            s   s                                          CH.sub.3    H     s            u   s                                          CH.sub.3    H     u            s   s                                          H           H     u            u   s                                          CH.sub.2    H     u            s   s                                          CH.sub.3    --    u            s   u                                          H           H     s            u   s                                          CH.sub.2    H     s            s   s                                          CH.sub.3    --    s            s   u                                          ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- O                                                                  R.sub.3 -- C N                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 872S,3R-3-Acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Following the procedure of Example 76, but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepaneand employing one equivalent of hydroxylamine hydrochloride,2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneis obtained.

EXAMPLE 882S,3R-3-Acetoxy-2-methyl-6-cyanomethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Following the procedure of Example 77 but substituting an equivalentamount of2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3R-3-acetoxy-2-methyl-6-cyanomethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared by the method of Example 88 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR65##                                                                      R.sub.4       R.sub.5                                                                             a          b   c                                        ______________________________________                                        CH.sub.3    H     u            u   s                                          H           H     s            s   s                                          CH.sub.3    H     s            s   s                                          H           --    s            s   u                                          H           H     u            s   s                                          CH.sub.3    H     s            u   s                                          CH.sub.3    H     u            s   s                                          H           H     u            u   s                                          CH.sub.2    H     u            s   s                                          CH.sub.3    --    u            s   u                                          H           H     s            u   s                                          CH.sub.2    H     s            s   s                                          CH.sub.3    --    s            s   u                                          ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- OAc                                                                R.sub.3 -- C N                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 892S,3R,6R-6-Ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olis dissolved in benzene (40 ml.); p-toluenesulfonic acid (181 mg.) isadded and the resulting suspension is stirred at room temperature for 24hrs. The benzene solution is decanted, the residue washed with benzene(3×) and the combined benzene layers evaporated to dryness in vacuo at35°. The resulting reddish-brown residue (605 mg.) is chromatographed ona Silicar column using chloroform as the eluting solvent. The majornon-polar fraction is eluted to afford2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(235 mg.).

IR-(neat) 5.85μ; NMR (CDCl₃) δ1.04, 1.31, 1.63 and 1.76 (CH₃); AB qcentered at 3.51; 5.0-6.2 (vinyl H).

EXAMPLE 902S,3R,6R-6-Ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 89, but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepaneis obtained.

EXAMPLE 912S,3R,6S-6-Ethyl-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane

2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(235 mg.) is dissolved in absolute ethanol (200 ml.), 10%palladium/carbon (200 mg.) is added and the resulting suspensionhydrogenated at 25 psi for 1 hr. The palladium/carbon is filtered, andthe filtrate is evaporated to dryness to give2S,3R,6S-6-ethyl-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane(237 mg.)

IR (neat) 5.85μ; NMR (CDCl₃) 0.8-1.35 (CH₃);

AB q centered at 3.5; no vinyl H.

EXAMPLE 922S,3R,6S-6-Ethyl-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-3,6-oxidooxepane

Following the procedure of Example 91, but substituting an equivalentamount of2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,2S,3R,6S-6-ethyl-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-3,6-oxidooxepaneis obtained.

EXAMPLE 932S,3R,6R-6-Ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 40 but substituting an equivalentamount of2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane-3-ol,2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepaneis obtained.

EXAMPLES 94 AND 952S,3R,6R-6-Ethenyl-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-3,6-oxidooxepane

and

2S,3R,6R-6-Ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Examples 41 and 42 but substituting anequivalent amount of2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepanefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol,2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-3,6-oxidooxepaneand2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-3,6-oxidooxepaneare obtained. The compounds are separated by chromatography.

EXAMPLE 962S,3R,6S-6-Ethyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 35 but substituting an equivalentamount of2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(6,7-oxido-5-oxo-4,7,8-trimethylnonyl)-oxepan-3-ol,2S,3R,6S-6-ethyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepaneis obtained. The reaction is stopped after an equivalent of hydrogen isabsorbed.

EXAMPLE 972S,3R,6S-6-(1,2-Dibromoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane

Bromine (160 mg.) is added to a mixture of2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane(320 mg.) and methylene chloride (20 ml.) at 0°. The resulting mixtureis stirred for 5 mins., then treated with water (30 ml.) and methylenechloride (30 ml.). The organic layer is dried and evaporated to give2S,3R,6S-6-(1,2-dibromoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane.

EXAMPLE 982S,3R,6S-6-(1,2-Dibromoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane

A mixture of2S,3R,6S-6-(1,2-dibromoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane(470 mg.), palladium on carbon (5%, 20 mg.) and glacial acetic acid (30ml.) is hydrogenated at atmospheric pressure for 16 hrs. The resultingmixture is filtered through Celite and the filtrate is treated withwater (50 ml.) and ether (100 ml.). The organic phase is washed with 10%sodium carbonate solution (3×100 ml.) dried and evaporated to give2S,3R,6S-6-(1,2-dibromoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane.

EXAMPLE 992S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane

To a mixture of2S,3R,6S-6-(1,2-dibromoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane(470 mg.) and glacial acetic acid (20 ml.) is added an excess of zincdust (200 mg.) at 0° and the resulting mixture is stirred for 1 hour.The reaction mixture is filtered through a pad of Celite and thefiltrate is treated with water (50 ml.) and ether (100 ml.). The organicphase is washed with 10% sodium carbonate solution (3×100 ml.), driedand evaporated to give2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane.

EXAMPLE 1002S,3R,6S-6-Ethyl-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 93 but substituting2S,3R,6S-6-ethyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor an equivalent amount of2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,2S,3R,6S-6-ethyl-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepaneis obtained.

EXAMPLE 1012S,3R,6R-6-Ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-3,6-oxidooxepane

Following the procedure of Example 98 but substituting an equivalentamount of2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-6-nonenyl)-3,6-oxidooxepane,2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethylnonyl)-3,6-oxidooxepaneis obtained.

EXAMPLE 1022S,3R,6S-6-Ethyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 96 but substituting an equivalentamount of2S,3R,6R-6-ethenyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-6-ethenyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,2S,3R,6S-6-ethyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepaneis obtained.

EXAMPLES 103 AND 1042S,3R,6S-6-Ethyl-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-3,6-oxidooxepane

and

2S,3R,6S-6-Ethyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Examples 41 and 42 but substituting anequivalent amount of2S,3R,6S-6-ethyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-6-nonenyl)-3,6-oxidooxepanefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepane-3-olaffords2S,3R,6S-6-ethyl-2-methyl-2-(4,8-dimethyl-7-methylene-5-oxononyl)-3,6-oxidooxepaneand2S,3R,6S-6-ethyl-2-methyl-2-(5-oxo-4,7,8-trimethyl-7-nonenyl)-3,6-oxidooxepane.The compounds are separated by chromatography.

EXAMPLE 1052S,3R,6R-6-(2-Oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(1.0 g.) in methylene chloride (250 ml.) is stirred with manganesedioxide (2.2 g.) at room temperature under nitrogen for 17 hours. Themanganese dioxide is filtered, washed with methylene chloride and thesolvent is removed in vacuo.

The residue is plate chromatographed on silica gel, using ethylacetate-chloroform (4:1) as the developing solvent. The less polar UVabsorbing band is eluted with ethyl acetate-chloroform (4:1) to afford2S,3R,6R-6-(2-oxo-ethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(850 mg.):

IR (neat)μ: 3.63 (CHO), 5.80 (>C═O, H--C═O);

NMR (CDCl₃)δ: 1.06 (d,J=7 Hz, 3H, (CH--CH₃), 1.30 (s, 3H, --O--COCH₃),1.63 and 1.75 [each s, each 3H, C═C--(CH₃)₂ ], 2.60 (d,J=2 Hz, 2H, --CH₂--CHO), 3.13 (d,J=8 Hz, 2H, --CH₂ --CO); 3.29 and 3.73 (each d, J=11 Hz,2H, ##STR66## 5.25 [m, 1H, H--C═(CH₃)₂ ], 9.78 (t, J=2 Hz, 1H, --CH₂--CH).

The following compounds are prepared by the method of Example 105 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR67##                                                                          R.sub.3 R.sub.4        b   c                                            ______________________________________                                        CH.sub.3  H              u     s                                              CH.sub.3  H              s     s                                              H         H              u     s                                              CH.sub.2  H              s     s                                              CH.sub.3  --             s     u                                              H         OH             u     s                                              H         OH             s     s                                              ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1062S,3R,6R-6-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

A suspension of sodium borohydride (69.8 mg.) in benzene (15 ml.) istreated with acetic acid (92 mg.) and refluxed for 1 hour under nitrogento afford a clear solution of sodium triacetoxyborohydride. To thissolution is added a solution of2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(158 mg.) in benzene (5 ml.) and the mixture refluxed for 5 hours undernitrogen. The solvent is removed in vacuo, the residue diluted withwater and extracted with methylene chloride. Removal of the solvent fromthe dried organic phase affords a residue which is plate chromatographedon silica gel, using ethyl acetate:chloroform (4:1) as the developingsolvent. The major band is eluted with ethyl acetate to afford2S,3R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(121 mg.):

IR (neat)μ: 2.85 (OH), 5.82 (C═O); NMR (CDCl₃)δ: 1.06 (d,J=6 Hz, 3H, CH₃--CH), 1.27 (s, 3H, 2--CH₃), 1.60 and 1.73 [each s, each 3H, (CH₃)₂--C═C)], 3.09 (d,J=7 Hz, 2H, CH₂ --CO), 3.17 and 3.75 (each d, J=11 Hz,each 1H, 7--CH₂), 3.75 (t, 3H, CH₂ --OH and 3--H), 5.06-5.43 (broad m,1H, HC--C═(CH₃)₂

The following compounds are prepared by the method of Example 106 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

    ______________________________________                                         ##STR68##                                                                      EXAMPLE       R.sub.3 R.sub.4   b   c                                       ______________________________________                                                  CH.sub.3                                                                            H           u     s                                                     H     H           s     s                                                     CH.sub.3                                                                            H           s     s                                                     H     H           u     s                                                     CH.sub.2                                                                            H           s     s                                                     CH.sub.3                                                                            --          s     u                                                     H     OH          u     s                                                     H     OH          s     s                                           ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- CH.sub.2 OH                                                        u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1072S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

To a stirred suspension of pre-reduced platinum oxide (500 mg.) in water(75 ml.) is added sodium bicarbonate (1.58 g.),2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(600 mg.) in acetone (48 ml.) and water (117 ml.). The mixture isstirred briskly at room temperature protected from light under an oxygenatmosphere (in an atmospheric pressure hydrogenation apparatus for 24hours). Platinum metal is removed by filtration on a pad of Celite andwashed with 10% acetone in water. The combined filtrate and washings areevaporated to dryness in vacuo. The residue is dissolved in water (˜125ml.) and extracted with ethyl acetate (2×100 ml.). The aqueous layer isacidified to pH 3 with dil. hydrochloric acid and quickly extracted withethyl acetate (2×100 ml.). The organic layer is washed with brine, driedand evaporated in vacuo to afford an oily residue (0.681 g.) which isplate chromatographed on silica gel, using isopropanol-chloroform-aceticacid (36:363:1) as the eluting solvent. The least polar band is elutedwith isopropanol-chloroform (1:6) to afford2S,3R-6R-2-methyl-(6-carboxymethyl)-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(170 mg):

IR (neat) μ: 2.8-3.3 (broad, OH), 5.8 (shoulder) 5.85 (C═O) and COOH);NMR (CDCl₃)δ: 1.03 (d, J=7 Hz, 3H, CH₃ --CH), ##STR69##

The following compounds are prepared by the method of Example 107 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR70##                                                                      EXAMPLE       R.sub.3 R.sub.4   b   c                                       ______________________________________                                                  CH.sub.3                                                                            H           u     s                                                     CH.sub.3                                                                            H           s     s                                                     H     H           u     s                                                     CH.sub.2                                                                            H           s     s                                                     CH.sub.3                                                                            --          s     u                                                     H     OH          s     s                                           ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- CO.sub.2 H                                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1082S,3R,6R-6-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

A solution of2S,3R,6R-6-(oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(200 mg.) in ethanol (10 ml.) is treated with sodium borohydride (55 mg)at room temperature under nitrogen for 18 hours. Ethanol is removed invacuo, the residue diluted with water (5 ml.) and neutralized with 5%hydrochloric acid. The aqueous solution is extracted with methylenechloride (2×50 ml.) and the organic layer dried and the solvent removedin vacuo. The residue is plate chromatographed on silica gel usingisopropanol chloroform (1:9) as the developing solvent. The major bandis eluted with isopropanol-chloroform (1:1) to afford2S,3R,6R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(152 mg.):

IR (neat) μ: 2.90 (OH); NMR (CDCl₃)δ: 0.88 (d, J=6 Hz, 3H, CH₃--CH--CH--C--OH), 1.32 (s, 3H, --O--C--CH₃), 1.63 and 1.72 [each s, each3H, (CH₃)₂ --C═CH], ##STR71## are clearly visible and 3.20-3.40 (broadm, 1H, H13 C--OH) is diffused; 5.12 [m, 1H, (CH₃)₂ --C═CH9 .

The following compounds are prepared by the method of Example 108 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R,6R-6-(oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

    ______________________________________                                         ##STR72##                                                                          R.sub.3 R.sub.4        b   c                                            ______________________________________                                        CH.sub.3  H              u     s                                              H         H              s     s                                              CH.sub.3  H              s     s                                              H         H              u     s                                              CH.sub.2  H              s     s                                              CH.sub.3  --             s     u                                              H         OH             u     s                                              H         OH             s     s                                              ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- CH.sub.2 OH                                                        u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1092S,3R,6R-6-(2-Oxoethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

(A) Following the procedure of Example 105 but substituting anequivalent amount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(81% yield) is obtained.

IR (neat) μ: 2.86 (OH), 3.64 (CHO) and 5.81 (C═O); NMR (CDCl₃ -TMS) δ:0.90 (d, J=6 Hz, 3H, CH₃ --CH), 1.33 (s, 3H, CH₃ --C--), 1.65 and 1.73[both s, 3H each, (CH₃)₂ C═CH], 2.60 (d, J=2 Hz, 2H, CH₂ --CHO), 3.29and 3.74 (each d, J=11 Hz, each 1H, O--CH₂ --C), 9.80 (t, J=2 Hz, 1H,CHO).

(B) A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol(340 mg.) in t-butanol (20 ml.) is treated with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (340 mg.) and the mixtureheated to reflux for 124 hours. Removal of the solvent followed bychromatography affords2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared by the methods of Example 109 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR73##                                                                      EXAMPLE    R.sub.3   R.sub.4                                                                            b      c   Method                                 ______________________________________                                               CH.sub.3                                                                              H      u        s   B                                                 H       H      s        s   A                                                 CH.sub.3                                                                              H      s        s   A                                                 H       H      u        s   B                                                 CH.sub.2                                                                              H      s        s   A                                                 CH.sub.3                                                                              --     s        u   A                                                 H       OH     u        s   B                                                 H       OH     s        s   B                                          ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- CHO                                                                u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1102S,3R,6R-2-Methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

To a stirred suspension of pre-reduced platinum oxide (400 mg.) in water(28 ml.) is added sodium bicarbonate (650 mg.) and2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol(260 mg.) in acetone (12 ml.) and water 20 ml.). The mixture is stirredbriskly at room temperature under an oxygen atmosphere for 20 hrs.Platinum metal is removed by filtration on a pad of Celite and washedwith 10% acetone/water. The combined filtrate and washings areevaporated to dryness in vacuo. The residue is dissolved in water (150ml.) and extracted with ethyl acetate (2×175 ml.). The aqueous layer isacidified to pH 3 with dilute hydrochloric acid and quickly extractedwith ethyl acetate (2×150 ml.). The ethyl acetate layer is washed withbrine, dried and evaporated in vacuo to afford an oily residue (0.240g.) which is plate chromatographed on silica gel usingisopropanol:chloroform (1:8) with a drop of acetic acid as the elutingsolvent. The major band is eluted with isopropanol:chloroform (1:1) toafford2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(192 mg.):

IR (neat) μ: 2.89 (OH), 5.8 (C═O and COOH); NMR (CDCL₃)δ: 0.88 (d, J=7Hz, 3H, CH₃ --CH--CH--OH), 1.31 (s, 3H, CH₃ --C--O), 1.63 and 1.71 [eachs, each 3H, (CH₃)₂ --C═CH)], 2.60 (s, 2H, CH₂ --CO₂ H), 3.39 and 3.76(each d, J=11 Hz, 2H, --C--CH₂ --O--C) 3.85 (m, 1H, H--C--O--C) 4.91,5.16 [m,1H,(CH₃)₂ --C═CH) and 6.03 (broad s, 1H, COOH)].

The following compounds are prepared by the method of Example 110 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR74##                                                                          R.sub.3 R.sub.4        b   c                                            ______________________________________                                        CH.sub.3  H              u     s                                              H         H              s     s                                              CH.sub.3  H              s     s                                              H         H              u     s                                              CH.sub.2  H              s     s                                              CH.sub.3  --             s     u                                              H         OH             u     s                                              H         OH             s     s                                              ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- COOH                                                               u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1112S,3R,6R-2Methyl-6-carbmethoxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

N-methylnitrosourea (1 g.) is slowly added (3 mins.) to a well shaken,cold (0°-5°) mixture of 40% aqueous potassium hydroxide (3 ml.) andeither (10 ml.). When all the solid is dissolved (˜15 min.), theethereal solution of diazomethane is decanted, dried (potassiumhydroxide pellets) and added to a solution of2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(77 mg.) in either (5 ml.). After all the excess diazomethane isevaporated, the ether solution is washed with water, dried and the etherremoved under a stream of nitrogen to afford2S,3R,6R-2-methyl-6-carbmethoxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(74 mg.):

IR (neat) μ: 2.85 (OH), 5.75 (COOMe); NMR (CDCl₃)δ: 0.85 (d, J=7 Hz, 3H,CH₃ --CH, ##STR75##

EXAMPLE 1122S,3R,6R-2-Methyl-6-carbmethoxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 111 but substituting an equivalentamount of2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane,2S,3R,6R-2-methyl-6-carbmethoxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepaneis obtained.

EXAMPLE 1132S,3R,6R-2-Methyl-6-cyanomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure for the synthesis of2S,3R-3-acetoxy-2-methyl-6-cyanomethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefrom2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanebut substituting an equivalent amount of2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanein Example 87 affords the corresponding oxime which is dehydrated asdescribed in Example 88.

The following compounds are prepared by the method of Example 113 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

    ______________________________________                                         ##STR76##                                                                          R.sub.3 R.sub.4        b   c                                            ______________________________________                                        CH.sub.3  H              u     s                                              H         H              s     s                                              CH.sub.3  H              s     s                                              H         H              u     s                                              CH.sub.2  H              s     s                                              CH.sub.3  --             s     u                                              ______________________________________                                         R.sub.1 -- O                                                                  R.sub.2 -- CN                                                                 u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1142S,3R,6R-2-Methyl-6-cyanomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 18 but substituting an equivalentamount of2S,3R,6R-2-methyl-6-cyanomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olaffords2S,3R,6R-2-methyl-6-cyanomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared by the method of Example 114 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R,6R-2-methyl-6-cyanomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

    ______________________________________                                         ##STR77##                                                                          R.sub.3 R.sub.4        b   c                                            ______________________________________                                        CH.sub.3  H              u     s                                              H         H              s     s                                              CH.sub.3  H              s     s                                              H         H              u     s                                              CH.sub.2  H              s     s                                              CH.sub.3  --             s     u                                              ______________________________________                                         R.sub.1 -- OH                                                                 R.sub.2 -- CN                                                                 u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1152S,3R,6R-2-Methyl-6-carbamoylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedures of Examples 65 and 66 for the synthesis of2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefrom2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanebut substituting an equivalent amount of2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanein Example 65,2S,3R,6R-2-methyl-6carbamoylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepaneis obtained.

The following compounds are prepared by the method of Example 115 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

    ______________________________________                                         ##STR78##                                                                        R.sub.3 R.sub.4 R.sub.5  R.sub.6 b   c                                    ______________________________________                                        CH.sub.3                                                                              H       H          H       u   s                                      H       H       CH.sub.3   CH.sub.3                                                                              s   s                                      CH.sub.3                                                                              H       C.sub.2 H.sub.5                                                                          H       s   s                                      H       H       C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5                                                                       u   s                                      CH.sub.2                                                                              H       CH.sub.2 C.sub.6 H.sub.5                                                                 H       s   s                                      CH.sub.3                                                                              --      CH.sub.3   H       s   u                                      ______________________________________                                         R.sub.1 -- O                                                                  ##STR79##                                                                                                                                                   u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1162S,3R,6R-2-Methyl-6-carbamoylmethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 114 but substituting an equivalentamount of2S,3R,6R-2-methyl-6-carbamoylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6S-2-methyl-6-cyanomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,2S,3R,6R-2-methyl-6-carbamoylmethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepaneis obtained.

The following compounds are prepared by the method of Example 116 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R,6R-2-methyl-6-carbamoylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

    ______________________________________                                         ##STR80##                                                                    R.sub.3 R.sub.4  R.sub.5     R.sub.6                                                                              b   c                                     ______________________________________                                        CH.sub.3                                                                              H        H           H      u   s                                     H       H        CH.sub.3    CH.sub.3                                                                             s   s                                     CH.sub.3                                                                              H        C.sub.2 H.sub.5                                                                           H      s   s                                     H       H        C.sub.6 H.sub.5                                                                           C.sub.6 H.sub.5                                                                      u   s                                     CH.sub.2                                                                              H        CH.sub.2 C.sub.6 H.sub.5                                                                  H      s   s                                     CH.sub.3                                                                              --       CH.sub.3    H      s   u                                     ______________________________________                                         R.sub.1OH                                                                     ##STR81##                                                                                                                                                   u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1172S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxyimino-7-nonenyl)-oxepane

Following the procedure of Example 76 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S,3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxyimino-7-nonenyl)-oxepaneis obtained.

The following examples are prepared by the procedure of Example 117 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR82##                                                                    R.sub.1                                                                             R.sub.2                                                                             R.sub.3  R.sub.4                                                                           R.sub.5                                                                          a  b  c                                           __________________________________________________________________________    NOH   OH    CH.sub.2 OH                                                                            H   -- u  s  u                                           OH    NOH   CH.sub.2 OH                                                                            H   -- u  s  u                                           OAc   OAc   CHNOH    H   -- u  s  u                                           NOH   NOH   CHNOH    H   -- u  s  u                                           NOH   OH    CH.sub.2 OH                                                                            CH.sub.3                                                                          H  u  u  s                                           NOH   OH    CH.sub.2 OH                                                                            H   H  s  s  s                                           NOH   OH    CH.sub.2 OH                                                                            CH.sub.3                                                                          H  s  s  s                                           NOH   OH    CH.sub.2 OH                                                                            H   -- s  s  u                                           NOH   OH    CH.sub.2 OH                                                                            CH.sub.3                                                                          H  s  u  s                                           NOH   OH    CH.sub.2 OH                                                                            CH.sub.3                                                                          -- u  s  u                                           NOH   OH    CH.sub.2 OH                                                                            CH.sub.2                                                                          H  u  s  s                                           NOH   OH    CH.sub.2 OH                                                                            CH.sub.3                                                                          -- s  s  u                                            ##STR83##                                                                          OAc   CHNOH    H   -- u  s  u                                           __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the procedure of Example 117 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR84##                                                                    R.sub.1  R.sub.2       R.sub.3 R.sub.4                                                                             b   c                                    ______________________________________                                        NOH      CH.sub.2      H       --    s   u                                    NOH      CH.sub.2      CH.sub.2                                                                              H     s   s                                    NOH      CH.sub.2      CH.sub.3                                                                              --    s   u                                    NOH      CH.sub.3      H       --    s   u                                    NOH      CH.sub.2      H       H     s   s                                    NOH      CH.sub.2      CH.sub.3                                                                              H     s   s                                    NOH      CH.sub.2 OH   H       --    s   u                                    O        CHNOH         H       --    s   u                                    OH       CHNOH         H       --    s   u                                    NOH      CO.sub.2 CH.sub. 3                                                                          H       --    s   u                                    NOH      CN            H       --    s   u                                    NOH      CONHNH.sub.2  H       --    s   u                                    NOH      CONHN(CH.sub.3).sub.2                                                                       H                                                       ##STR85##                                                                             CHNOH         H       --    s   u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1182S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(p-nitrophenoxy)imino-7-nonenyl]-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) in absolute ethanol (15 ml) is treated withp-nitrophenylhydroxylamine (250 mg) and a trace of hydrochloric acid.After stirring for 72 hrs at 25° C., the ethanol is evaporated and themixture is purified by chromatography to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(p-nitrophenoxy)imino-7-nonenyl]-oxepane.

Similarly, by substituting other aromatic hydroxylamines forp-nitrophenylhydroxylamine in the above procedure, the correspondingoximes are formed. Thus, phenylhydroxylamine anddinitrophenylhydroxylamine afford the phenoxyimino anddinitrophenoxyimino compounds respectively.

The following compound is prepared according to the method of Example118 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR86##                                                                    R.sub.1                                                                            R.sub.2                                                                              R.sub.3            R.sub.4                                                                           R.sub.5                                                                           a   b   c                              ______________________________________                                        O    O      CHNOC.sub.6 H.sub.4 p-NO.sub.2                                                                   H   --  u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the procedure of Example 118 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR87##                                                                    R.sub.1         R.sub.2  R.sub.3 R.sub.4                                                                             b   c                                  ______________________________________                                        NOC.sub.6 H.sub.5                                                                             CH.sub.2 H       H     u   s                                  NOC.sub.6 H.sub.4 p-NO.sub.2                                                                  CH.sub.3 CH.sub.3                                                                              --    s   u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1192S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methoxyimino-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) in anhydrous pyridine (2 ml) is treated with methoxylaminehydrochloride (105 mg) under nitrogen. After standing for 24 hours at25° C., the reaction mixture is poured into water and extracted withchloroform. The chloroform extract is washed with dilute aqueous sodiumbicarbonate and saturated salt solution, dried and evaporated to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methoxyimino-7-nonenyl)-oxepane.

Similarly by substituting other alkoxyamine hydrochlorides formethoxylamine hydrochloride in the procedure of Example 119, thecorresponding oximes are formed. Thus, ethoxylamine hydrochloride,butoxylamine hydrochloride and O-phenoxy hydroxylamine hydrochlorideafford the ethoxyimino, butoxyimino and phenoxyimino compoundsrespectively.

The following compounds are prepared by the procedure of Example 119 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR88##                                                                    R.sub.1  R.sub.2                                                                              R.sub.3  R.sub.4                                                                          R.sub.5                                                                          a b c                                          __________________________________________________________________________    NOCH.sub.3                                                                             NOCH.sub.3                                                                           CH.sub.2 OH                                                                            H  -- u s u                                          NOCH.sub.2 C.sub.6 H.sub.5                                                             OH     CH.sub.2 OH                                                                            H  H  u s s                                          NOCH.sub.2 C.sub.6 H.sub.5                                                             OH     CH.sub.2 OH                                                                            CH.sub.3                                                                         H  u s s                                          NOCH.sub.3                                                                             OH     CH.sub.2 OH                                                                            H  H  u u s                                          NOCH.sub.3                                                                             OAc    CO.sub.2 H                                                                             H  -- u s u                                          NOCH.sub.3                                                                             OAc    CO.sub.2 CH.sub.3                                                                      H  -- u s u                                           NOCH.sub.3                                                                            OAc    CONHCH.sub.3                                                                           H  -- u s u                                          NOCH.sub.3                                                                             OAc    CONH.sub.2                                                                             H  -- u s u                                          NOCH.sub.3                                                                             OAc    CONHNH.sub.2                                                                           H  -- u s u                                          NOCH.sub.3                                                                             OAc    CN       H  -- u s u                                          NOCH.sub.3                                                                             OTHP   CH.sub.2 OTHP                                                                          H  -- u s u                                          NOCH.sub.3                                                                             OAc    CH.sub.2 ONO.sub.2                                                                     H  -- u s u                                          NOCH.sub.3                                                                             OAc    CH.sub.2 H  -- u s u                                                          OPO(OCH.sub.3).sub.2                                          NOCH.sub.3                                                                             OAc    CH.sub.2OCH.sub.3                                                                      H  -- u s u                                          NOCH.sub.3                                                                             OAc    CH.sub.2Br                                                                             H  -- u s u                                          NOCH.sub.3                                                                             OAc    CH.sub.2 SH                                                                            H  -- u s u                                           ##STR89##                                                                             OAc    CHNOCH.sub.3                                                                           H  -- u s u                                           ##STR90##                                                                             OAc    CHNOCH.sub.3                                                                           H  -- u s u                                            NOCH.sub.3                                                                           OH     CH.sub.2 OH                                                                            H  OH u u s                                          __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 119 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR91##                                                                    R.sub.1        R.sub.2   R.sub.3 R.sub.4                                                                           b     c                                  ______________________________________                                        NOCH.sub.3     CH.sub.2  CH.sub.3                                                                              H   u     s                                  NOCH.sub.2 C.sub.6 H.sub.5                                                                   CH.sub.3  CH.sub.3                                                                              H   s     s                                  NOCH.sub.3     CH.sub.3  H       H   u     s                                   ##STR92##     CH.sub.3  CH.sub.3                                                                              H   u     s                                    NOCH.sub.3   CO.sub.2 H                                                                              H       --  s     u                                  NOC.sub.2 H.sub.5                                                                            CH.sub.2 OH                                                                             H       --  s     u                                  NOCH.sub.2 C.sub.6 H.sub.5                                                                   CONH.sub.2                                                                              H       --  s     u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1202S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-benzoyloxyimino-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxyimino-7-nonenyl)-oxepane(437 mg) in anhydrous benzene (3 ml) and anhydrous pyridine (72 mg) istreated with benzoyl chloride (140 mg). The mixture is refluxed for 3hrs, cooled, additional benzene is added and the reaction mixture iswashed with water. The organic phase is dried over potassium carbonateand evaporated to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-benzoyloxyimino-7-nonenyl)-oxepane.

Similarly, by substituting other acyl chlorides for benzoyl chloride, inthe procedure of Example 120, the corresponding acyloximes are formed.Thus acetyl chloride and butyryl chloride afford the acetoxyimino andbutyryloxymino compounds respectively.

The following compounds are prepared according to the procedure ofExample 120 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxyimino-7-nonenyl)-oxepaneand employing the appropriate acylating agent.

    ______________________________________                                         ##STR93##                                                                    R.sub.1                                                                            R.sub.2  R.sub.3      R.sub.4                                                                             R.sub.5                                                                           a     b   c                              ______________________________________                                        O    OAc      CHNOAc       H     --  u     s   u                              O    OAc      CHNOBz       H     --  u     s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                Bz -- benzoyl                                                            

The following compounds are prepared according to the procedure ofExample 120 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxyimino-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR94##                                                                    R.sub.1   R.sub.2    R.sub.3 R.sub.4 b   c                                    ______________________________________                                        NOAc      CH.sub.3   H       H       s   s                                    NOAc      CH.sub.3   CH.sub.2                                                                              H       s   s                                    NOBz      CH.sub.3   H       H       s   s                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                Bz -- benzoyl                                                            

EXAMPLE 1212S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylhydrazono-7-nonenyl)-oxepane

A mixture of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) and N,N-dimethylhydrazine (85 mg) is heated for 4 hrs at 70° C.and then at room temperature for 48 hrs. Ether and water are added andthe layers separated. The organic layer is dried and evaporated toafford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylhydrazono-7-nonenyl)-oxepane.

Similarly by substituting other hydrazines for N,N-dimethylhydrazine inthe procedure of Example 121, the corresponding hydrazones are formed.Thus, hydrazine and N,N-dibutylhydrazine afford the correspondinghydrazono and dibutylhydrazono compounds respectively.

The following compounds are prepared according to the procedure ofExample 121 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR95##                                                                    R.sub.1      R.sub.2      R.sub.3       R.sub.4                                                                           R.sub.5                                                                         a b c                           __________________________________________________________________________    NNH.sub.2    OH           CH.sub.2 OH   H   --                                                                              u s u                           NN(CH.sub.3).sub.2                                                                         NN(CH.sub.3).sub.2                                                                         CH.sub.2 OH   H   --                                                                              u s u                           OH           NN(CH.sub.3).sub.2                                                                         CH.sub.2 OH   H   --                                                                              u s u                           NNHCH.sub.2C.sub.6 H.sub.5                                                                 NNHCH.sub.2C.sub.6 H.sub.5                                                                 CHNNHCH.sub.2C.sub.6 H.sub.5                                                                H   --                                                                              u s u                           NN(CH.sub.3).sub.2                                                                         OH           CH.sub.2 OH   CH.sub.3                                                                          H u u s                           NNH.sub.2    OH           CH.sub.2 OH   CH.sub.3                                                                          H s s s                           NN(CH.sub.3).sub.2                                                                         OH           CH.sub.2 OH   H   --                                                                              s s u                           NNHCH.sub.2C.sub.6 H.sub.5                                                                 OH           CH.sub.2 OH   H   --                                                                              u s u                           NNH.sub.2    OH           CH.sub.2 OH   CH.sub.3                                                                          H s u s                           NN(CH.sub.3).sub.2                                                                         OH           CH.sub.2 OH   CH.sub.3                                                                          --                                                                              u s u                           NN(CH.sub.3).sub.2                                                                         OH           CH.sub.2 OH   CH.sub.2                                                                          H u s s                           NN(CH.sub.3).sub.2                                                                         OH           CH.sub.2 OH   CH.sub.3                                                                          --                                                                              s s u                           NN(CH.sub.3).sub.2                                                                         OAc          CO.sub.2 C.sub.2 H.sub.5                                                                    H   --                                                                              u s u                           NNHCONH.sub.2                                                                              OAc          CONH.sub.2    H   --                                                                              u s u                           NNH.sub.2    OAc          CONHNH.sub.2  H   --                                                                              u s u                           NN(CH.sub.3).sub.2                                                                         OCH.sub.3    CH.sub.2 OCH.sub.3                                                                          H   --                                                                              u s u                           __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 121 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR96##                                                                      R.sub.1          R.sub.2     R.sub.3                                                                             R.sub.4                                                                           b   c                                ______________________________________                                        NNH.sub.2      CH.sub.2    H       --  s   u                                  NN(CH.sub.3).sub.2                                                                           CH.sub.2    CH.sub.3                                                                              H   u   s                                  NNHCH.sub.2C.sub.6 H.sub.5                                                                   CH.sub.2    H       H   u   s                                  NN(CH.sub.3).sub.2                                                                           CH.sub.2    CH.sub.3                                                                              --  s   u                                  NN(CH.sub.3).sub.2                                                                           CH.sub.3    CH.sub.2                                                                              H   s   s                                   ##STR97##     CH.sub.3    CH.sub.3                                                                              H   u   s                                  NN(CH.sub.3).sub.2                                                                           CH.sub.2 OH H       --  s   u                                   ##STR98##     CH.sub.3    CH.sub.2                                                                              H   s   s                                  NN(CH.sub.3).sub.2                                                                           CN          H       --  s   u                                  NNH.sub.2      CONH.NH.sub.2                                                                             H       --  s   u                                   ##STR99##     CHNNH.sub.2 H       --  s   u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1222S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-carbamoylhydrazono-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) in methanol (1 ml) is treated with a solution of semicarbazide(17 ml) prepared by dissolving semicarbazide hydrochloride (2.5 g) andpyridine (1.8 ml) in water (15 ml) and methanol (60 ml). The mixture isrefluxed for 18 hrs. The methanol is evaporated in vacuo and the residuepartitioned between ether and water. The organic extract is dried andevaporated to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-carbamoylhydrazono-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 122 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR100##                                                                   R.sub.1    R.sub.2                                                                          R.sub.3     R.sub.4                                                                          R.sub.5                                                                          a b c                                         __________________________________________________________________________    NNHCONH.sub.2                                                                            OH CH.sub.2 OH CH.sub.3                                                                         H  u s s                                         NNHCONH.sub.2                                                                            OH CH.sub.2 OH H  H  u u s                                         NNHCONH.sub.2                                                                            OAc                                                                              CONH.sub.2  H  -- u s u                                         NNHCONH.sub.2                                                                            OAc                                                                              CN          H  -- u s u                                         NNHCONH.sub.2                                                                            OAc                                                                              CH.sub.2ONO.sub.2                                                                         H  -- u s u                                         NNHCONH.sub.2                                                                            OAc                                                                              CH.sub.2OPO(OCH.sub.3).sub.2                                                              H  -- u s u                                         NNHCONH.sub.2                                                                            OAc                                                                              CH.sub.2OCH.sub.3                                                                         H  -- u s u                                         NNHCONH.sub.2                                                                            OAc                                                                              CH.sub.2N(CH.sub.3).sub.2                                                                 H  -- u s u                                         NNHCONH.sub.2                                                                            OAc                                                                              CH.sub.2SH  H  -- u s u                                          ##STR101##                                                                              OAc                                                                              CHNNHCONH.sub.2                                                                           H  -- u s u                                           CH.sub.2 OAc                                                                              CHNNHCONH.sub.2                                                                           H  -- u s u                                          ##STR102##                                                                              OAc                                                                              CHNNHCONH.sub.2                                                                           H  -- u s u                                          ##STR103##                                                                              OAc                                                                              CHNNHCONH.sub.2                                                                           H  -- u s u                                           NNHCONH.sub.2                                                                          OH CH.sub.2 OH H  OH u u s                                         __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 122 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR104##                                                                     R.sub.1        R.sub.2         R.sub.3                                                                             R.sub.4 b c                            ______________________________________                                        NNHCONH.sub.2                                                                              CH.sub.2        CH.sub.2                                                                              Hs s                                     NNHCONH.sub.2                                                                              CH.sub.3        H       --s u                                    NNHCONH.sub.2                                                                              CH.sub.2        H       Hs s                                     NNHCONH.sub.2                                                                              CH.sub.3        H       Hu s                                     O            CHNNHCONH.sub.2 H       --s u                                    NNHCONH.sub.2                                                                              CO.sub.2 H      H       --s u                                    NNHCONH.sub.2                                                                              CH.sub.2 OH     H       --s u                                    NNHCONH.sub.2                                                                              CO.sub.2 CH.sub.3                                                                             H       --s u                                    ______________________________________                                         u -- unsaturated                                                              s --  saturated                                                          

EXAMPLE 1232S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2,4-dinitrophenylhydrazono)-7-nonenyl]-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) in ethanol (10 ml) is treated with a standard acidic solutionof 2,4-dinitrophenylhydrazine in aqueous ethanol at 50° C. for 3 hrs.The reaction mixture is cooled to room temperature and water (35 ml) isadded. The solvent is decanted and the residue washed with additionalwater until it is neutral. The residue is then dissolved in methylenechloride, washed with saturated salt solution, dried and evaporated togive2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(2,4-dinitrophenylhydrazono)-7-nonenyl]-oxepane.

Similarly, by substituting other aromatic hydrazines for2,4-dinitrophenylhydrazine in the procedure of Example 123, thecorresponding aromatic hydrazones are formed. Thus phenylhydrazine andp-bromophenylhydrazine afford the corresponding phenylhydrazone andp-bromophenylhydrazone compounds respectively.

The following compounds are prepared according to the procedure ofExample 123 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR105##                                                                   R.sub.1      R.sub.2                                                                          R.sub.3       R.sub.4                                                                         R.sub.5                                                                         a b c                                       __________________________________________________________________________    OH           OAc                                                                              CHNNHC.sub.6 H.sub.5                                                                        H --                                                                              u s u                                       NNHC.sub.6 H.sub.3 (NO.sub.2).sub.2                                                        OAc                                                                              CO.sub.2 H    H --                                                                              u s u                                       NNHC.sub.6 H.sub.3 (NO.sub.2).sub.2                                                        OAc                                                                              CO.sub.2 CH.sub.3                                                                           H --                                                                              u s u                                       O            OAc                                                                              CHNNHC.sub.6 H.sub.3 (NO.sub.2).sub.2                                                       H --                                                                              u s u                                       __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 123 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR106##                                                                     R.sub.1           R.sub.2     R.sub.3                                                                            R.sub.4                                                                            b c                                 ______________________________________                                        NNHC.sub.6 H.sub.3 (NO.sub.2).sub.2                                                           CH.sub.3    H      H    s s                                   NNHC.sub.6 H.sub.5                                                                            CH.sub.3    CH.sub.3                                                                             --   s u                                   NNHC.sub.6 H.sub.4p-NO.sub.2                                                                  CH.sub.2    CH.sub.3                                                                             H    s s                                   NNHC.sub.6 H.sub.3 (NO.sub.2).sub.2                                                           CONHCH.sub.3                                                                              H      --   s u                                   ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1242S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-bromobenzenesulfonylhydrazono-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) in absolute ethanol (20 ml) is treated withp-bromobenzenesulfonylhydrazide (427 mg) and a trace of hydrochloricacid. After stirring at room temperature for 18 hr, the solution isevaporated, the residue taken up in methylene chloride, filtered andevaporated to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-bromobenzenesulfonylhydrazono-7-nonenyl)-oxepane.

Similarly, by substituting other sulfonylhydrazides forp-bromobenzenesulfonylhydrazide in the procedure of Example 124, thecorresponding sulfonylhydrazones are formed. Thus,benzenesulfonylhydrazide and p-toluenesulfonylhydrazide afford thebenzenesulfonylhydrazono and toluenesulfonylhydrazono compoundsrespectively.

The following compounds are prepared according to the method of Example124 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-acetoxyethylidene-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate sulfonylhydrazide.

    __________________________________________________________________________     ##STR107##                                                                   R.sub.1         R.sub.2                                                                          R.sub.3       R.sub.4                                                                         R.sub.5                                                                         a b c                                    __________________________________________________________________________    OH              O  CHNNHSO.sub.2C.sub.6 H.sub.5                                                                H --                                                                              u s u                                    NNHSO.sub.2C.sub.6 H.sub.4p-CH.sub.3                                                          OH CH.sub.2 OH   H H s s s                                    __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 124 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR108##                                                                     R.sub.1             R.sub.2   R.sub.3                                                                            R.sub.4                                                                           b   c                                ______________________________________                                        NNHSO.sub.2C.sub.6 H.sub.4p-CH.sub.3                                                            CH.sub.3  CH.sub.3                                                                             H   s   s                                  NNHSO.sub.2C.sub.6 H.sub.4p-CH.sub.3                                                            CONH.sub.2                                                                              H      --  s   u                                  ______________________________________                                    

EXAMPLE 1252S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-amino-4,8-dimethyl-7-nonenyl)oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) and ammonium acetate (770 mg.) in methanol (3 ml.) is treatedwith lithium cyanohydridoborate (33 mg.). After stirring for 48 hrs. at25°, concentrated hydrochloric acid is added until a pH<2 is reached andthe methanol is evaporated. The residue is dissolved in water andextracted with ether. The aqueous solution is cooled, made basic withsodium carbonate and quickly extracted with ether. The ethereal extractis dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-amino-4,8-dimethyl-7-nonenyl)-oxepane.

The following compounds are prepared by the procedure of Example 125 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR109##                                                                     R.sub.1 R.sub.2 R.sub.3 R.sub.4                                                                              R.sub.5                                                                            a    b    c                             ______________________________________                                        NH.sub.2                                                                            OH      CH.sub.2OH                                                                              H      --   u    s    u                               NH.sub.2                                                                            NH.sub.2                                                                              CH.sub.2OAc                                                                             H      --   u    s    u                               OH    OAc     CH.sub.2NH.sub.2                                                                        H      --   u    s    u                               NH.sub.2                                                                            NH.sub.2                                                                              CH.sub.2NH.sub.2                                                                        H      --   u    s    u                               NH.sub.2                                                                            OH      CH.sub.2OH                                                                              CH.sub.3                                                                             H    u    u    s                               NH.sub.2                                                                            OAc     CH.sub.2OAc                                                                             H      --   s    s    u                               NH.sub.2                                                                            OH      CH.sub.2OH                                                                              CH.sub.3                                                                             H    s    u    s                               NH.sub.2                                                                            OH      CH.sub.2OH                                                                              CH.sub.3                                                                             H    u    s    s                               NH.sub.2                                                                            OH      CH.sub.2OH                                                                              CH.sub.3                                                                             --   u    s    u                               NH.sub.2                                                                            OH      CH.sub.2OH                                                                              CH.sub.2                                                                             H    u    s    s                               NH.sub.2                                                                            OAc     CH.sub.2OAc                                                                             CH.sub.3                                                                             --   s    s    u                               NH.sub.2                                                                            OH      CH.sub.2OH                                                                              CH.sub.2                                                                             H    s    s    s                               NH.sub.2                                                                            OAc     CO.sub.2 H                                                                              CH.sub.3                                                                             H    u    u    s                               NH.sub.2                                                                            OAc     CO.sub.2 C.sub.2 H.sub.5                                                                CH.sub.3                                                                             H    u    u    s                               NH.sub.2                                                                            OAc     CO.sub.2 C.sub.2 H.sub.5                                                                CH.sub.3                                                                             H    s    u    s                               NH.sub.2                                                                            OAc     CONH.sub.2                                                                              CH.sub.3                                                                             H    u    u    s                               NH.sub.2                                                                            OAc     CN        CH.sub.3                                                                             H    u    u    s                               NH.sub.2                                                                            OAc     CN        CH.sub.3                                                                             H    s    u    s                               NH.sub. 2                                                                           OH      CH.sub.2OH                                                                              H      OH   u    u    s                                ##STR110##                                                                         NH.sub.2                                                                              CH.sub.2OAc                                                                             H      --   u    s    u                                ##STR111##                                                                         OAc     CH.sub.2NH.sub.2                                                                        H      --   u    s    u                                 NH.sub.2                                                                          OAc     CH.sub.2Br                                                                              H      --   u    s    u                               CH.sub.2                                                                            OAc     CH.sub.2 NH.sub.2                                                                       H      --   u    s    u                                ##STR112##                                                                         OAc     CH.sub.2NH.sub.2                                                                        H      --   u    s    u                               ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the method of Example 125 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR113##                                                                       R.sub.1  R.sub.2     R.sub.3                                                                              R.sub.4                                                                             b    c                                  ______________________________________                                        NH.sub.2 CH.sub.2NH.sub.2                                                                          H        --    s    u                                    OAc      CH.sub.2NH.sub.2                                                                          H        --    s    u                                    NH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                                  H        --    s    u                                    NH.sub.2 CO.sub.2 CH.sub.3                                                                         H        --    s    u                                    NH.sub.2 CO.sub.2 C.sub.4 H.sub.9                                                                  H        --    s    u                                    NH.sub.2 CONH.sub.2  H        --    s    u                                    NH.sub.2 CH.sub.2    CH.sub.3 H     u    s                                    NH.sub.2 CH.sub.2    CH.sub.3 --    s    u                                    NH.sub.2  CH.sub.2 NH.sub.2                                                                        CH.sub.3 H     u    s                                    NH.sub.2 CH.sub.2    H        OH    u    s                                    NH.sub.2 CONHC.sub.2 H.sub.5                                                                       H        --    s    u                                    CH.sub.2 CH.sub.2NH.sub.2                                                                          H        --    s    u                                     ##STR114##                                                                            CH.sub.2NH.sub.2                                                                          H        --    s    u                                      NH.sub.2                                                                             CH.sub.2SCH.sub.3                                                                         H        --    s    u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1262S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-benzoylamino-4,8-dimethyl-7-nonenyl)-oxepane

To a mixture of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-amino-4,8-dimethyl-7-nonenyl)-oxepane(422 mg.) and N,N-dimethylaniline (0.14 ml.) is added benzoyl chloride(0.155 ml.). The mixture is heated and stirred at 90° for 3 hrs., cooledand poured into dilute hydrochloric acid and extracted with ether. Theethereal extract is dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-benzoylamino-4,8-dimethyl-7-nonenyl)-oxepane.

Similarly, by substituting other acyl chlorides for benzoyl chloride inthe procedure of Example 126, the corresponding acylamines are obtained.Thus acetyl chloride and butyryl chloride afford the 5-acetoxy and5-butyryloxy compounds respectively.

EXAMPLE 1272S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methylamino-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) and anhydrous methylamine (190 mg.) in methanol (2.5 ml.) istreated with 5N hydrochloric acid (0.4 ml.) in methanol and lithiumcyanohydridoborate (30 mg.). The solution is stirred at 25° for 72 hrs.,then worked-up as described in Example 125 to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methylamino-7-nonenyl)-oxepane.

Similarly, by substituting other primary amines for methylamine in theprocedure of Example 127, the corresponding primary amines are formed.Thus ethylamine and phenylamine afford the 5-ethylamino and5-phenylamino compounds respectively.

The following examples are prepared by the method of Example 127 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate primary amine.

    ______________________________________                                         ##STR115##                                                                     R.sub.1   R.sub.2   R.sub.3  R.sub.4                                                                            R.sub.5                                                                            a   b   c                            ______________________________________                                        OH      NHCH.sub.3                                                                              CH.sub.2 NHCH.sub.3                                                                      H    --   u   s   u                              NHCH.sub.3                                                                            OH        CH.sub.2OH H    H    s   s   s                              NHCH.sub.3                                                                            OAc       CH.sub.2OAc                                                                              H    H    s   s   s                              NHCH.sub.3                                                                            OH        CH.sub.2OH H    H    u   u   s                              NHCH.sub.3                                                                            OAc       CO.sub.2 H H    --   u   s   u                              NHCH.sub.3                                                                            OAc       CO.sub.2 CH.sub.3                                                                        H    --   u   s   u                              NHCH.sub.3                                                                            OAc       CO.sub.2 C.sub. 2 H.sub.5                                                                H    --   u   s   u                              NHCH.sub.3                                                                            OAc       CN         H    --   u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the procedure of Example 127 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate primary amine.

    ______________________________________                                         ##STR116##                                                                       R.sub.1    R.sub.2      R.sub.3                                                                             R.sub.4                                                                            b    c                                 ______________________________________                                        NHCH.sub.3 CH.sub.2     H       --   s    u                                   NHCH.sub.3 CN           H       --   s    u                                   NHCH.sub.3 CH.sub.2NHCH.sub.3                                                                         H       --   s    u                                   ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1282S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylamino-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) and anhydrous dimethylamine (270 mg.) in absolute methanol(2.5 ml.) is treated with 5N hydrochloric acid (0.4 ml.) in methanol andlithium cyanohydridoborate (33 mg.). The solution is stirred for 72 hrs.then worked-up as in Example 125 to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylamino-7-nonenyl)-oxepane.

Similarly, by substituting other secondary amines for dimethylamine inthe procedure of Example 128, the corresponding secondary amines areobtained. Thus dipropylamine and dibenzylamine afford the5-dipropylamino and 5-dibenzylamino compounds respectively.

The following compounds are prepared by the procedure of Example 128 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate secondary amine.

    ______________________________________                                         ##STR117##                                                                     R.sub.1    R.sub.2   R.sub.3  R.sub.4                                                                            R.sub.5                                                                           a   b   c                            ______________________________________                                        OH       N(CH.sub.3).sub.2                                                                       CH.sub.2OH H    --  u   s   u                              N(CH.sub.3).sub.2                                                                      OH        CH.sub.2OH H    H   s   s   s                              N(CH.sub.3).sub.2                                                                      OH        CH.sub.2OH H    H   s   u   s                              N(CH.sub.3).sub.2                                                                      OAc       CO.sub.2 H H    H   u   u   s                              N(CH.sub.3).sub.2                                                                      N(CH.sub.3).sub.2                                                                       CONH.sub.2 H    --  u   s   u                              ______________________________________                                         u -- unsaturated                                                              s --  saturated                                                          

The following compounds are prepared by the procedure of Example 128 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate secondary amine.

    ______________________________________                                         ##STR118##                                                                       R.sub.1   R.sub.2       R.sub.3                                                                             R.sub.4                                                                            b    c                                 ______________________________________                                        N(CH.sub.3).sub.2                                                                       CH.sub.3      H       --   s    u                                    ##STR119##                                                                             CH.sub.2N(CH.sub.3).sub.2                                                                   H       --   s    u                                   ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1292S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-trimethylammonio-7-nonenyl)-oxepaneiodide

A solution of2S,3R-3-acetoxy-6-(2-acetoxy-ethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylamino-7-nonenyl)-oxepane(450 mg.) in methyl iodide (3 ml.) is allowed to stand at 40° C. for 48hrs. The excess methyl iodide is evaporated in vacuo to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-trimethylammonio-7-nonenyl)-oxepaneiodide.

The following compounds are prepared by the procedure of Example 129 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylamino-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR120##                                                                     R.sub.1     R.sub.2 R.sub.3 R.sub.4                                                                            R.sub.5                                                                            a    b   c                            ______________________________________                                         ##STR121##                                                                             OAc     CO.sub.2 CH.sub.3                                                                       H    --   u    s   u                               ##STR122##                                                                             OH      CH.sub.2 OH                                                                             H    H    s    s   s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compound is prepared by the procedure of Example 129 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-dimethylamino-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR123##                                                                     R.sub.1           R.sub.2  R.sub.3                                                                             R.sub.4                                                                            b    c                                ______________________________________                                        N.sup.+ (CH.sub.3).sub.3 I.sup.-                                                              CH.sub.3 H       --   s    u                                  N.sup.+ (CH.sub.3).sub.2 CH.sub.2 C.sub.6 H.sub.5 I.sup.-                                     CH.sub.3 H       --   s    u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1302S-3-(Azacyclohex-1-yl)-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3-oxepene

A solution of2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-one(338 mg) and piperidine (170 mg) in anhydrous benzene (25 ml) isrefluxed for 12 hrs employing a Dean-Stark water separator. The benzeneand excess piperidine are evaporated in vacuo to give2S-3-(azacyclohex-1-yl)-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3-oxepene.

EXAMPLE 1312S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-isopropylimino-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg) and isopropylamine (60 mg) in benzene (20 ml) is treated withone drop of concentrated hydrochloric acid and the reaction mixturerefluxed with a water separator for 12 hrs. The benzene is evaporated togive2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-isopropylimino-7-nonenyl)-oxepane.

EXAMPLE 1322S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane

To a mixture of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(338 mg), pyridine (1 ml) and ether (10 ml) is added trimethylsilylchloride (224 mg) at 0° under nitrogen. After the addition is completed,the mixture is allowed to warm to room temperature and stirred for 10mins. The resulting mixture is then treated with ether (30 ml) and water(20 ml). The organic layer is washed with saturated cupric sulfate (3×20ml), dried and evaporated in vacuo to give2S,3R-6-(2-trimethyl-siloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane.

The following compounds are prepared according to the procedure ofExample 132 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR124##                                                                     R.sub.1  R.sub.2  R.sub.3  R.sub.4                                                                             R.sub.5                                                                             a   b   c                            ______________________________________                                        OTMS   O        CHO        H     --    u   s   u                              O      OTMS     CH.sub.2 OTMS                                                                            CH.sub.3                                                                            H     s   s   s                              O      OTMS     CH.sub.2 OTMS                                                                            CH.sub.2                                                                            H     u   s   s                              OTMS   OAc      CO.sub.2 C.sub.4 H.sub.9                                                                 H     --    u   s   u                               ##STR125##                                                                          OTMS     CH.sub.2 OTMS                                                                            H     --    u   s   u                                CH.sub.2                                                                           OTMS     CH.sub.2 OTMS                                                                            H     --    u   s   u                               ##STR126##                                                                          OTMS     CH.sub.2 OTMS                                                                            H     --    u   s   u                                O    OTMS     CH.sub.2 OTMS                                                                            H     OTMS  u   u   s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                TMS -- trimethylsiloxy                                                   

The following compounds are prepared according to the procedure ofExample 132 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR127##                                                                       R.sub.1   R.sub.2     R.sub.3                                                                              R.sub.4                                                                            b    c                                  ______________________________________                                        OTMS      CH.sub.2    CH.sub.3 H    u    s                                    OTMS      CH.sub.2    CH.sub.2 H    s    s                                    OTMS      CH.sub.3    CH.sub.3 --   s    u                                    OTMS      CO.sub.2 CH.sub.3                                                                         H        --   s    u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1332S,3R-3-Acetoxy-6-(2-methoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

(A) Following the procedure of Example 141, but substituting anequivalent amount of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanethe 2-bromoethylidene derivative is obtained. A mixture of sodium amide(39 mg) and tetrahydrofuran (10 ml) is treated with dry methanol (32 mg)in tetrahydrofuran (1 ml) at 0° under argon. The 2-bromoethylidenederivative (450 mg) is added and the resulting mixture is refluxed for 2hrs. The mixture is treated with water (20 ml) and ether (50 ml) and theorganic layer dried and evaporated to afford2S,3R-3-acetoxy-6-(2-methoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

Similarly, by substituting other alcohols for methanol in the aboveprocedure, the corresponding ethers are formed. Thus, phenol, ethanoland cyclohexanol afford the phenyl ether, ethyl ether and cyclohexylether respectively.

(B) To a mixture of sodium amide (39 mg) and tetrahydrofuran (20 ml) isadded2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane(400 mg) in tetrahydrofuran (1 ml) at 0° under argon. The mixture isallowed to warm to room temperature and is treated with an excess ofmethyl iodide (1 ml). The resulting mixture is stirred overnight andthen treated with water (30 ml) and ether (50 ml). The organic layer isdried and evaporated to afford2S,3R-3-acetoxy-6-(2-methoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane.

Similarly by substituting other halides for methyl iodide in thisprocedure, the corresponding ethers are formed. Thus, allyl bromide,benzyl bromide and ethyl iodide afford the allyl ether, benzyl ether andethyl ether respectively.

The following compounds are prepared according to the procedure ofExample 133 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneand employing the appropriate alkyl halide.

    ______________________________________                                         ##STR128##                                                                     R.sub.1    R.sub.2   R.sub.3    R.sub.4                                                                            R.sub.5                                                                           a b c                              ______________________________________                                        OCH.sub.3                                                                              OAc       CHO          H    --  u s u                                OC.sub.5 H.sub.11                                                                      OC.sub.5 H.sub.11                                                                       CH.sub.2OC.sub.5 H.sub.11                                                                  H    --  u s u                                O        OCH.sub.3 CH.sub.2OCH.sub.3                                                                          H    H   sss                                  O        OC.sub.3 H.sub.7                                                                        CH.sub.2 OC.sub.3 H.sub.7                                                                  H    H   u ss                                 O        OC.sub.2 H.sub.5                                                                        CH.sub.2OC.sub.2 H.sub.5                                                                   CH.sub.3                                                                           H   sus                                  O        OCH.sub.3 CH.sub.2 OCH.sub.3                                                                         CH.sub.3                                                                           H   sss                                  O        OCH.sub.3 CH.sub.2 OCH.sub.3                                                                         CH.sub.3                                                                           --  u s u                                OCH.sub.3                                                                              OAc       CO.sub.2 CH.sub.3                                                                          H    --  u s u                                OCH.sub.3                                                                              OAc       CN           H    --  u s u                                OCH.sub.2 C.sub.6 H.sub.5                                                              OAc       CHO          H    --  u s u                                 ##STR129##                                                                            OAc       CH.sub.2 OC.sub.6 H.sub.5                                                                  H    --  u s u                                ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 133 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneand employing the appropriate alkyl halide.

    ______________________________________                                         ##STR130##                                                                     R.sub.1      R.sub.2       R.sub.3                                                                             R.sub.4                                                                            b    c                                ______________________________________                                        OCH.sub.3  CH.sub.3      H       H    s    s                                  OCH.sub.3  CH.sub.3      CH.sub.3                                                                              H    s    s                                  OC.sub.2 H.sub.5                                                                         CH.sub.2      H       H    u    s                                  OC.sub.3 H.sub.7                                                                         CH.sub.3      H       --   s    u                                  OCH.sub.2C.sub.6 H.sub.5                                                                 CH.sub.2      H       H    s    s                                  OC.sub.6 H.sub.5                                                                         CH.sub.3      CH.sub.2                                                                              H    s    s                                  OC.sub.2 H.sub.5                                                                         CH.sub.2      CH.sub.3                                                                              H    s    s                                  OC.sub.4 H.sub.9                                                                         CH.sub.3      CH.sub.3                                                                              H    u    s                                   OCH.sub.3 CO.sub.2 CH.sub.3                                                                           H       --   s    u                                  OCH.sub.3  CONH.sub.2    H       --   s    u                                  OCH.sub.3  CONHNH.sub.2  H       --   s    u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1342S,3R-6-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(600 mg) in benzene (5 ml) is treated, while stirring, with dihydropyran(7.8 ml) and p-toluenesulfonic acid monohydrate (3 mg) at roomtemperature under nitrogen for 1.2 hrs. The benzene solution is washedwith 10% aqueous sodium carbonate solution, dried and the solventremoved in vacuo to afford the crude product (871 mg) which ischromatographed on a SilicAR column using ethyl acetate-hexane (1:20) asthe eluting solvent. The major fraction is eluted to afford2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane(395 mg).

IR (neat) very weak OH at 2.95μ, C═O at 5.81μ NMR _(TMS) ^(CDCl).sbsp.3δ1.05 (d, J=7 Hz, 3H, CH--CH₃); 1.10 (s, 3H, O--C--CH₃); 1.23 (s, 3H,unassigned); 2.60 (s, 2H, unassigned); 3.11 (d, J=7 Hz, CH₂ --CO); 4.05(s, 2H, CH₂ --O--R); 4.58 (m, C═CH--CH₂ --OTHP); 5.10-5.20 [m, 2H,(CH₃)₂ --C═CH and C═CH--CH₂ --OTHP].

The following compounds are prepared according to the procedure ofExample 134 by substituting an equivalent amount of the startingmaterial for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR131##                                                                     R.sub.1   R.sub.2   R.sub.3   R.sub.4                                                                            R.sub.5                                                                           a   b   c                            ______________________________________                                        O       O         CH.sub.2 OTHP                                                                             H    --  u   s   u                              OTHP    O         CH.sub.2 OTHP                                                                             H    --  s   s   u                              O       OTHP      CH.sub.2 OTHP                                                                             CH.sub.3                                                                           H   u   u   s                              O       OTHP      CH.sub.2 OTHP                                                                             H    --  s   s   u                              O       OTHP      CH.sub.2 OTHP                                                                             H    H   u   u   s                              O       OTHP      CH.sub.2 OTHP                                                                             CH.sub.3                                                                           --  u   s   u                              OTHP    OAc       CONH.sub.2  H    --  u   s   u                              OTHP    OAc       CON(CH.sub.3).sub.2                                                                       H    --  u   s   u                              O       OH        CH.sub.2 OTHP                                                                             H    --  u   s   u                              O       OTHP      CH.sub.2 Br H    --  u   s   u                              O       OTHP      CH.sub.2 SCH.sub.3                                                                        H    --  u   s   u                               ##STR132##                                                                           OTHP      CH.sub.2 OTHP                                                                             H    --  u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                THP -- tetrahydropyran2-yloxy                                            

The following compounds are prepared according to the procedure ofExample 134 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR133##                                                                       R.sub.1     R.sub.2    R.sub.3                                                                             R.sub.4                                                                            b    c                                  ______________________________________                                        OTHP        CH.sub.2   H       --   s    u                                    OTHP        CH.sub.2   CH.sub.3                                                                              --   s    u                                    OTHP        CH.sub.3   H       H    u    s                                    O           CH.sub.2 OTHP                                                                            H       --   s    u                                    OCH.sub.2 C.sub.6 H.sub.5                                                                 CH.sub.2 OTHP                                                                            H       --   s    u                                    OTHP        CHO        H       --   s    u                                    OTHP        CN         H       --   s    u                                    OTHP        CONH.sub.2 H       --   s    u                                     ##STR134## CH.sub.2 OTHP                                                                            H       --   s    u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                THP -- tetrahydropyran2-yloxy                                            

EXAMPLE 134'2S,3R-6-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-tetrahydropyran-2-yloxy-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane

To a mixture of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol(450 mg) and methylene chloride (10 ml) is added dihydropyran (2.25 ml)and p-toluenesulfonic acid (5.0 mg) at room temperature under nitrogenfor 1.2 hr. The organic phase is washed with 10% sodium bicarbonatesolution (3×15 ml) and dried. The solvent is removed in vacuo to give abrown oily residue which is plate chromatographed on silica gel, usingethyl acetate-cyclohexane (1:4) as the developing solvent. The majorband is eluted with ethyl acetate-cyclohexane (1:1) to afford2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-tetrahydropyran-2-yloxy-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane(329 mg): ir (neat); 9.3μ (C--O); nmr (CDCl₃,δ): 4.03 (m, 2H, CH₂--O--R), 4.56 (m, 2H, C═CH--CH₂ --OTHP), 5.1 to 5.5 (m, 2H, (CH₃)₂--C═CH and C═CH--CH₂ --OTHP).

EXAMPLE 1352S,3R-3-Acetoxy-6-(2-sulfooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg) and N-cyclohexylsulfamic acid (600 mg) in anhydrous pyridine(20 ml) is heated at 60° C. for 4 hours. The reaction mixture is dilutedwith water (1.0 ml) and heated to 100 ° for 10 minutes to decomposeexcess N-cyclohexylsulfamic acid. The pyridine is evaporated, theresidue is dissolved in water (10 ml) and passed through Dowex 50H⁺resin to afford2S,3R-3-acetoxy-6-(2-sulfooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

The following compound is prepared according to the procedure of Example135 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR135##                                                                     R.sub.1 R.sub.2 R.sub.3   R.sub.4                                                                            R.sub.5                                                                            a    b    c                             ______________________________________                                        O     O       CH.sub.2 OSO.sub.3 H                                                                      H    --   u    s    u                               ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 135 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR136##                                                                     EXAMPLE    R.sub.1   R.sub.2   R.sub.3                                                                             R.sub.4                                                                           b   c                              ______________________________________                                               OSO.sub.3 H                                                                           CH.sub.2    CH.sub.3                                                                              H   u   s                                         OSO.sub.3 H                                                                           CH.sub.3    CH.sub.2                                                                              H   s   s                                         OSO.sub.3 H                                                                           CH.sub.3    H       H   u   s                                         OSO.sub.3 H                                                                           CONH(CH.sub.3).sub.2                                                                      H       --  s   u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1362S,3R-3-Acetoxy-6-(2-sulfooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,triethylammonium salt

A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg) and purified triethylamine sulfur trioxide complex (210 mg) inpyridine (2 ml) is heated at 75° for 12 hours. After cooling, anhydrousether (50 ml) is added to the reaction mixture and the resultingsolution is allowed to stand in the cold for 1 hour. The ether isdecanted and the residue is chromatographed on silica gel to give2S,3R-3-acetoxy-6-(2-sulfooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,triethylammonium salt.

The following compounds are prepared according to the procedure ofExample 136 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR137##                                                                   R.sub.1   R.sub.2  R.sub.3     R.sub.4                                                                           R.sub.5                                                                         a b c                                    __________________________________________________________________________    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   --                                                                              u s u                                    OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                     O        CHO         H   --                                                                              u s u                                    OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                     OAc      CHO         H   --                                                                              u s u                                    OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                     OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   --                                                                              u s u                                    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               CH.sub.3                                                                          H u u s                                    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   H u s s                                    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               CH.sub.3                                                                          H u s s                                    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   H u u s                                    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               CH.sub.2                                                                          H u s s                                    O         OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               CH.sub.3                                                                          --                                                                              u s u                                    O         OSO.sub.3 NHCH.sub.3                                                                   CH.sub.2OTHP                                                                              H   --                                                                              u s u                                     ##STR138##                                                                             OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   --                                                                              u s u                                     ##STR139##                                                                             OSO.sub.3 NH(C.sub.2 H.sub.5 ).sub.3                                                   CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   --                                                                              u s u                                     ##STR140##                                                                             OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   --                                                                              u s u                                     ##STR141##                                                                             OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                    CH.sub.2OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                               H   --                                                                              u s u                                    __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                                THP -- tetrahydropyran2-yloxy                                            

The following compounds are prepared according to the procedure ofExample 136 by substituting an equivalent amount of the appropriatestarting material for2S,3R-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR142##                                                                     R.sub.1        R.sub.2   R.sub.3                                                                              R.sub.4                                                                            b    c                                 ______________________________________                                        OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                        CH.sub.3  H        H    s    s                                   OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                        CH.sub.3  CH.sub.2 H    s    s                                   OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                        CHO       H        --   s    u                                   OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                        CONH.sub.2                                                                              H        --   s    u                                   OSO.sub.3 NH(C.sub.2 H.sub.5).sub.3                                                        CONH      H        --   s    u                                                NH.sub.2                                                         ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1372S,3R-3-Acetoxy-6-(2-nitrooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Nitric acid (95%, 0.65 ml) is slowly added to acetic anhydride (1.98 ml)at -25° C. followed by the addition of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg) at -20° C. The stirred mixture is slowly warmed to 0°-5° C.within 20 minutes. The mixture is then poured over ice, neutralized withsodium bicarbonate and extracted with ether. The ether extract isevaporated in vacuo to afford2S,3R-3-acetoxy-6-(2-nitro-oxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 137 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR143##                                                                     R.sub.1  R.sub.2 R.sub.3 R.sub.4                                                                             R.sub.5                                                                            a    b    c                             ______________________________________                                        O      O       CH.sub.2 ONO.sub.2                                                                      H     --   u    s    u                               O      ONO.sub.2                                                                             CH.sub.2 ONO.sub.2                                                                      H     H    s    s    s                               O      ONO.sub.2                                                                             CH.sub.2 ONO.sub.2                                                                      H     --   s    s    u                               O      ONO.sub.2                                                                             CH.sub.2 ONO.sub.2                                                                      CH.sub.3                                                                            H    s    u    s                               ONO.sub.2                                                                            OAc     CO.sub.2 CH.sub.3                                                                       H     --   u    s    u                               ONO.sub.2                                                                            OAc     CONH.sub.2                                                                              H     --   u    s    u                               O      ONO.sub.2                                                                             CH.sub.2 Br                                                                             H     --   u    s    u                               ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 137 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR144##                                                                       R.sub.1   R.sub.2     R.sub.3                                                                            R.sub.4                                                                              b   c                                   ______________________________________                                        ONO.sub.2 CH.sub.2    H      H      u   s                                     ONO.sub.2 CH.sub.2    CH.sub.3                                                                             --     s   u                                     ONO.sub.2 CH.sub.2    H      H      s   s                                     ONO.sub.2 CH.sub.3    CH.sub.3                                                                             --     s   u                                     ONO.sub.2 CH.sub.3    CH.sub.3                                                                             H      u   s                                     O         CH.sub.2 ONO.sub.2                                                                        H      --     s   u                                     ONO.sub.2 CH.sub.2 ONO.sub.2                                                                        H      --     s   u                                     ONO.sub.2 CO.sub.2 CH.sub.3                                                                         H      --     s   u                                     CH.sub.2  CH.sub.2 ONO.sub.2                                                                        H      --     s   u                                     ______________________________________                                         u --  unsaturated                                                             s -- saturated                                                           

EXAMPLE 1382S,3R-3-Acetoxy-6-(2-phosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg) in dry tetrahydrofuran (10 ml) is added dropwise to a stirredsolution of pyrophosphoryl chloride (1 g) in dry tetrahydrofuran (5 ml)at 0°-5° C. After stirring at 0°-5° C. for 3 hours, the reaction mixtureis diluted with ice-cold water (75 ml) and the tetrahydrofuran isevaporated in vacuo. The product is extracted with ethyl acetate andafter washing with water, the solvent is removed in vacuo to afford2S,3R-3-acetoxy-6-(2-phosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

The following compound is prepared according to the procedure of Example138 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR145##                                                                     R.sub.1                                                                              R.sub.2    R.sub.3  R.sub.4                                                                            R.sub.5                                                                           a    b    c                             ______________________________________                                        O    OPO(OH).sub.2                                                                            CH.sub.2O  CH.sub.3                                                                           H   s    s    s                                               PO(OH).sub.2                                                  ______________________________________                                         s -- saturated                                                                u -- unsaturated                                                         

The following compound is prepared by the procedure of Example 138 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR146##                                                                       R.sub.1    R.sub.2     R.sub.3                                                                           R.sub.4                                                                              b   c                                   ______________________________________                                        OPO(OH).sub.2                                                                            CN          H     --     s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1392S,3R-3-Acetoxy-6-(2-phosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,disodium salt

A solution of2S,3R-3-acetoxy-6-(2-phosphonooxy-ethylidene)-2-methyl-2-(4,8-dimethyl-5oxo-7-nonenyl)-oxepane(500 mg) in methanol (10 ml) is adjusted to pH 10.5 by slow addition ofcold aqueous sodium hydroxide solution. Addition of ether affords2S,3R-3-acetoxy-6-(2-phosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,disodium salt, which is collected by filtration.

The following compound is prepared according to the procedure of Example139 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-phosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR147##                                                                     R.sub.1     R.sub.2  R.sub.3                                                                             R.sub.4                                                                           R.sub.5                                                                            a    b    c                             ______________________________________                                        OPO(ONa).sub.2                                                                          OAc      CO.sub.2 Na                                                                           H   --   u    s    u                               ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 139 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-phosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR148##                                                                       R.sub.1     R.sub.2   R.sub.3                                                                            R.sub.4                                                                              b   c                                   ______________________________________                                        OPO(ONa).sub.2                                                                            CH.sub.3  H      --     s   u                                     OPO(ONa).sub.2                                                                            CH.sub.3  CH.sub.3                                                                             H      s   s                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1402S,3R-3-Acetoxy-6-(2-dimethylphosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

To a stirred solution by phosphorous oxychloride (0.2 ml) in dry acetone(2 ml) at 0° is slowly added a solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg) and triethylamine (0.5 ml) in dry acetone (2 ml). After 1 hour,anhydrous methanol (1 ml) is slowly introduced and the mixture allowedto stir for 1 hour. Triethylamine hydrochloride is removed by filtrationand ether (30 ml) is added to the filtrate. The organic phase is washedwith 10% aqueous sodium bicarbonate, dried and evaporated to afford2S,3R-3-acetoxy-6-(2-dimethylphosphonooxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 140 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    __________________________________________________________________________     ##STR149##                                                                   R.sub.1  R.sub.2 R.sub.3    R.sub.4                                                                          R.sub.5                                                                         a  b  c                                      __________________________________________________________________________    OPO(OCH.sub.3).sub.2                                                                   O       CH.sub.2 OPO(OCH.sub.3).sub.2                                                            H  --                                                                              u  s  u                                      OPO(OCH.sub.3).sub.2                                                                   OAc     CONH.sub.2 H  --                                                                              u  s  u                                      O        OPO(OCH.sub.3).sub.2                                                                  CH.sub.2 OPO(OCH.sub.3).sub.2                                                            H  --                                                                              u  s  u                                      __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compound is prepared according to the procedure of Example140 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR150##                                                                       R.sub.1      R.sub.2   R.sub.3                                                                           R.sub.4                                                                              b   c                                   ______________________________________                                        OPO(OCH.sub.3).sub.2                                                                       CH.sub.2  H     --     s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1412S,3R-3-Acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

To a mixture of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(390 mg.), pyridine (2 ml.) and ether (30 ml.) is added an excess ofphosphorous tribromide (540 mg.) at 0° under nitrogen. The resultingmixture is stirred for 2 hours and poured into water (30 ml.). Themixture is then extracted with ether (3×30 ml.), the organic layers arecombined, washed with saturated curpic sulfate, dried and evaporated invacuo to give2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

Similarly, by substituting phosphorous trichloride for phosphoroustribromide in the procedure of Example 141, the corresponding chlorideis obtained.

The following compounds are prepared according to the procedure ofExample 141 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate phosphorus trihalide.

    ______________________________________                                         ##STR151##                                                                     R.sub.1  R.sub.2 R.sub.3   R.sub.4                                                                             R.sub.5                                                                             a   b   c                            ______________________________________                                        O      Br      CH.sub.2 Br H     --    u   s   u                              O      O       CH.sub.2 Cl H     --    u   s   u                                Cl                                                                                  ##STR152##                                                                            ##STR153## H     --    u   s   u -  Br O CH.sub.2                                                            Br H -- u s u                  Br     OAc     CH(OCH.sub.3).sub.2                                                                       H     --    u   s   u                              Br     Br      CH.sub.2 Br H     --    u   s   u                              O      Cl      CH.sub.2 Cl CH.sub.3                                                                            H     u   u   s                              O      Cl      CH.sub.2 Cl H     H     s   s   s                              O      Cl      CH.sub.2 Cl CH.sub.3                                                                            H     s   s   s                              O      Br      CH.sub.2 Br H     --    s   s   u                              O      Br      CH.sub.2 Br H     H     u   s   s                              O      Cl      CH.sub.2 Cl CH.sub.3                                                                            H     s   u   s                              O      Cl      CH.sub.2 Cl CH.sub.3                                                                            H     u   s   s                              O      Br      CH.sub.2 Br H     H     u   u   s                              O      Br      CH.sub.2 Br CH.sub.3                                                                            --    u   s   u                              O      Br      CH.sub.2 Br CH.sub.2                                                                            H     u   s   s                              O      Cl      CH.sub.2 Cl H     H     s   u   s                              O      Br      CH.sub.2 Br CH.sub.3                                                                            --    s   s   u                              O      Br      CH.sub.2 Br CH.sub.2                                                                            H     s   s   s                              Br     OAc     CO.sub.2 H  H     --    u   s   u                              Cl     OAc     CO.sub.2 H  CH.sub.3                                                                            H     u   u   s                              Br     OAc     CO.sub.2 H  H     H     u   u   s                              Cl     OAc     CO.sub.2 CH.sub.3                                                                         H     --    u   s   u                              Br     OAc     CO.sub.2 C.sub.2 H.sub.5                                                                  CH.sub.3                                                                            H     u   u   s                              Br     OAc     CO.sub.2C.sub.2 H.sub.5                                                                   H     --    u   s   u                              Br     OAc     CO.sub.2 C.sub.6 H.sub.5                                                                  CH.sub.3                                                                            H     s   u   s                              Cl     O       CONH.sub.2  H     --    u   s   u                              Br     OAc     CONH.sub.2  CH.sub.3                                                                            H     u   u   s                              Cl     OAc     CN          H     --    u   s   u                              Cl     OAc     C N         CH.sub.3                                                                            H     u   u   s                              Cl     OAc     CN          CH.sub.3                                                                            H     s   u   s                              O      Br      CH.sub.2 Br H     OH    u   u   s                               ##STR154##                                                                          Br      CH.sub.2 Br H     --    u   s   u                               ##STR155##                                                                          Cl      CH.sub.2 Cl H     H     s   s   s                                CH.sub.2                                                                           Br      CH.sub.2 Br H     --    u   s   u                                Br   OAc                                                                                    ##STR156## H     --    u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 141 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand employing the appropriate phosphorous trihalide.

    ______________________________________                                         ##STR157##                                                                     R.sub.1    R.sub.2     R.sub.3 R.sub.4                                                                             b     c                                ______________________________________                                        Br       CH.sub.2    H         --    s     u                                  Cl       CH.sub.3    H         --    s     u                                  Br       CH.sub.2 Br H         --    s     u                                  Br       HC(OCH.sub.3).sub.2                                                                       H         --    s     u                                  Cl       CO.sub.2 H  H         --    s     u                                  Cl       CN          H         --    s     u                                  Br       CO.sub.2 C.sub.2 H.sub.5                                                                  H         --    s     u                                  Br       CO.sub.2 C.sub.4 H.sub.9                                                                  H         --    s     u                                  Cl       CONH.sub.2  H         --    s     u                                  Br       CH.sub.2    CH.sub.3  H     u     s                                  Cl       CH.sub.2    CH.sub.3  --    s     u                                  Cl       CH.sub.2 Cl CH.sub.3  H     u     s                                  Cl       CH.sub.2    H         OH    u     s                                  Cl       CONHC.sub.2 H.sub.5                                                                       H         --    s     u                                  Br       CON(CH.sub.3).sub.2                                                                       H         --    s     u                                  O        CH.sub.2 Br H         --    s     u                                   ##STR158##                                                                            CH.sub.2 Br H         --    s     u                                   ##STR159##                                                                            CH.sub.2 Cl H         --    s     u                                    CH.sub.2                                                                             CH.sub.2 Br H         --    s     u                                  Br       CH.sub.2 OAc                                                                              H         --    s     u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1422S,3R-3-Acetoxy-6-(2-mercaptoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of thioacetic acid (78 mg.) in absolute ethanol (20 ml.) isneutralized with potassium hydroxide (56 mg.) and2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(440 mg.) is added at 0°. The reaction mixture is allowed to warm toroom temperature and stirred for 6 hours. The resulting mixture istreated with water (20 ml.) and the ethanol is removed in vacuo. Theresidue is extracted with ether; the combined organic phase is dried andevaporated to give2S,3R-3-acetoxy-6-(2-mercaptoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 142 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR160##                                                                     R.sub.1  R.sub.2  R.sub.3   R.sub.4                                                                             R.sub.5                                                                            a   b   c                            ______________________________________                                        O      SH(S)    CH.sub.2 SH H     --   u   s   u                              O      O        CH.sub.2 SH H     --   u   s   u                              SH     O        CHO         H     --   u   s   u                              SH     O        CH.sub.2 SH H     --   u   s   u                              SH     SH(S)    CH.sub.2 SH H     --   u   s   u                              O      SH(S)    CH.sub.2 SH CH.sub.3                                                                            H    u   u   s                              O      SH(S)    CH.sub.2 SH H     H    s   s   s                              O      SH(S)    CH.sub.2 SH CH.sub.3                                                                            H    s   s   s                              O      SH(S)    CH.sub.2 SH CH.sub.3                                                                            H    s   u   s                              O      SH(S)    CH.sub.2 SH CH.sub.3                                                                            H    u   s   s                              O      SH(S)    CH.sub.2 SH CH.sub.3                                                                            --   u   s   u                              O      SH(S)    CH.sub.2 SH H     H    s   u   s                              O      SH(S)    CH.sub.2 SH CH.sub.2                                                                            H    s   s   s                              SH     OAc      CO.sub.2 H  CH.sub.3                                                                            H    u   u   s                              SH     OAc      CO.sub.2 CH.sub.3                                                                         H     --   u   s   u                              SH     OAc      CON(CH.sub.3).sub.2                                                                       H     --   u   s   u                              SH     OAc      CON(CH.sub.3).sub.2                                                                       CH.sub.3                                                                            H    s   u   s                              SH     O        CONH.sub.2  H     --   u   s   u                              SH     OAc      CN          H     --   u   s   u                              SH     OAc      C N         CH.sub.3                                                                            H    u   u   s                              SH     OAc      CN          CH.sub.3                                                                            H    s   u   s                               ##STR161##                                                                          SH(S)    CH.sub.2 SH H     --   u   s   u                                CH.sub.2                                                                           SH(S)    CH.sub.2 SH H     --   u   s   u                              SH     SH(S)    CH.sub.2 OAc                                                                              H     --   u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                (S) = configuration at position 3                                        

The following compounds are prepared according to the procedure ofExample 142 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR162##                                                                     R.sub.1    R.sub.2     R.sub.3                                                                             R.sub.4 b   c                                  ______________________________________                                        SH       CH.sub.3    H       --      s   u                                    SH       CHO         H       --      s   u                                    SH       CO.sub.2 H  H       --      s   u                                    SH       CN          H       --      s   u                                    SH       CONH.sub.2  H       --      s   u                                    SH       CH.sub.2    CH.sub.3                                                                              --      s   u                                    SH       CH.sub.2 SH CH.sub.3                                                                              H       u   s                                    SH       CH.sub.2    H       OH      u   s                                    SH       CONHC.sub.2 H.sub.5                                                                       H       --      s   u                                    O        CH.sub.2 SH H       --      s   u                                     ##STR163##                                                                            CH.sub.2 SH H       --      s   u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1432S,3R-3-Acetoxy-6-(2-methylthioethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Methyl mercaptan (1 g.) is added to a mixture of sodium hydride (24 mg.)and tetrahydrofuran (10 ml.) at -20°. After 1 hour of stirring, themixture is allowed to warm to room temperature and stirred for 1 hour.To the resulting suspension2S,3R-3-acetoxy-6-(2-bromoethylidene)-2methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(450 mg.) in tetrahydrofuran is slowly added and the resulting mixtureis stirred for 16 hours. The mixture is treated with water (30 ml.) andether (60 ml.). The organic layer is dried and evaporated to afford2S,3R-3-acetoxy-6-(2-methylthioethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

Similarly, by substituting other mercaptans for methyl mercaptan in theprocedure of Example 143, the corresponding thioethers are obtained.Thus, cyclopentyl mercaptan, thiophenol and benzylmercaptan afford thecyclopentyl thioether, phenylthioether and benzylthioether respectively.

The following compounds are prepared according to the procedure ofExample 143 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR164##                                                                     R.sub.1  R.sub.2   R.sub.3  R.sub.4                                                                             R.sub.5                                                                            a   b   c                            ______________________________________                                        SCH.sub.3                                                                            OAc       CHO        H     --   u   s   u                              O      SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       H     --   s   s   u                              O      SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       H     H    u   s   s                              O      SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       H     H    u   u   s                              O      SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       CH.sub.3                                                                            H    u   s   s                              O      SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       CH.sub.3                                                                            --   s   s   u                              SCH.sub.3                                                                            OAc       CO.sub.2 H H     --   u   s   u                              SCH.sub.3                                                                            OAc       CO.sub.2 H H     H    u   u   s                              SCH.sub.3                                                                            OAc       CO.sub.2 C.sub.2 H.sub.5                                                                 CH.sub.3                                                                            H    u   u   s                              SCH.sub.3                                                                            OAc       CONH.sub.2 CH.sub.3                                                                            H    u   s   s                              O      SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       H     OH   u   u   s                               ##STR165##                                                                          SCH.sub.3 (S)                                                                           CH.sub.2 SCH.sub.3                                                                       H     H    s   s   s                                SCH.sub.3                                                                          OAc                                                                                      ##STR166##                                                                              H     --   u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                                (S) = configuration at position 3                                        

The following compounds are prepared according to the procedure ofExample 143 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR167##                                                                       R.sub.1   R.sub.2     R.sub.3 R.sub.4                                                                            b     c                                ______________________________________                                        SCH.sub.3 CH.sub.2    H         --   s     u                                  SCH.sub.3 CH.sub.2 SCH.sub.3                                                                        H         --   s     u                                  SCH.sub.3 CON(CH.sub.3).sub.2                                                                       H         --   s     u                                  SCH.sub.3 CO.sub.2 C.sub.4 H.sub.9                                                                  H         --   s     u                                  SCH.sub.3 CH.sub.2    CH.sub.3  H    u     s                                   ##STR168##                                                                             CH.sub.2 SCH.sub.3                                                                        H         --   s     u                                    CH.sub.2                                                                              CH.sub.2 SCH.sub.3                                                                        H         --   s     u                                  SCH.sub.3 CH.sub.2 OAc                                                                              H         --   s     u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1442S,3R-Acetoxy-6-(2-p-nitrophenylcarbamoyl-oxyethylidene)-2-methyl-2-(4,8-dimethyl-5oxo-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(380 mg.) in benzene (5 ml.) is treated with p-nitrophenylisocyanate(180 mg.) in benzene (5 ml.) at room temperature under nitrogen for 15minutes. Removal of the solvent affords2S,3R-3-acetoxy-6-(2-p-nitrophenylcarbamoyloxyethylidene)-2-methyl-2-(4,8-dimethyl-5oxo-7nonenyl)-oxepane.

Similary, by substituting other isocyanates for p-nitrophenylisocyanatein this procedure, the corresponding urethanes are obtained. Thus,methylisocyanate and phenylisocyanate afford the methyl urethane andphenyl urethane respectively.

EXAMPLE 1452S,3R-6-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-thioxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane

To a stirred solution of 2S,3R-6[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane(506 mg.) in pyridine (10 ml.), heated under nitrogen to ˜90°,phosphorous pentasulfide (556 mg.) is slowly added over a period of 10minutes. The reaction mixture is maintained at 90° for 12 hours, thencooled and poured into ice water and extracted with ether. The etherlayer is dried and evaporated to afford2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-thioxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane.

The following compounds are prepared according to the procedure ofExample 145 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane.

    ______________________________________                                         ##STR169##                                                                       R.sub.1                                                                              R.sub.2     R.sub.3                                                                             R.sub.4 b   c                                    ______________________________________                                        S      CH.sub.2    H       --      s   u                                      S      CH.sub.2    CH.sub.3                                                                              H       u   s                                      S      CH.sub.3    H       H       s   s                                      S      CH.sub.3    CH.sub.3                                                                              H       s   s                                      S      CH.sub.2    H       H       u   s                                      S      CH.sub.2    CH.sub.2                                                                              H       s   s                                      S      CH.sub.2    CH.sub.3                                                                              --      s   u                                      S      CH.sub.3    H       --      s   u                                      S      CH.sub.2    H       H       s   s                                      S      CH.sub.3    H       H       u   s                                      S      CH.sub.3    CH.sub.2                                                                              H       s   s                                      S      CH.sub.3    CH.sub.3                                                                              H       s   s                                      S      CH.sub.2    CH.sub.3                                                                              H       s   s                                      S      CH.sub.3    CH.sub.3                                                                              H       u   s                                      ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1462S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-thioxo-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 12 but substituting an equivalentamount of2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-thioxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepanefor2S-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-one,2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-thioxo-7-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 1472S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5,5-ethylenedioxy-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) in anhydrous benzene (25 ml.), ethylene glycol (1 g.) andp-toluenesulfonic acid monohydrate (19 mg.) is heated at reflux for 16hours employing a Dean-Stark trap. The suspension is cooled to roomtemperature. Solid sodium carbonate (35 mg.) is added followed by water(50 ml.) and ether (50 ml.). The phases are separated, the aqueous layerextracted with additional ether and the combined organic extracts arewashed with saturated salt solution, dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5,5-ethylenedioxy-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 147 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-methyl-2-(4,8-dimethyl5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR170##                                                                     R.sub.1   R.sub.2  R.sub.3  R.sub.4                                                                             R.sub.5                                                                            a   b   c                            ______________________________________                                         ##STR171##                                                                           OH       CH.sub.2 OH                                                                              H     --   u   s   u                               ##STR172##                                                                            ##STR173##                                                                            CH.sub.2 OH                                                                              H     --   u   s   u                               ##STR174##                                                                           OAc                                                                                     ##STR175##                                                                              H     --   u   s   u                               ##STR176##                                                                            ##STR177##                                                                             ##STR178##                                                                              H     --   u   s   u                               ##STR179##                                                                           OAc      CH.sub.2 OAc                                                                             CH.sub.3                                                                            H    u   u   s                                 OAc                                                                                 ##STR180##                                                                            CH.sub.2 OAc                                                                             H     H    u   s   s                               ##STR181##                                                                           OH       CH.sub.2 OH                                                                              CH.sub.3                                                                            H    s   u   s                               ##STR182##                                                                           OH       CH.sub.2 OH                                                                              H     H    u   u   s                               ##STR183##                                                                           OAc      CH.sub.2 OAc                                                                             CH.sub.3                                                                            --   s   s   u                               ##STR184##                                                                           OAc      CONH.sub.2 H     --   u   s   u                               ##STR185##                                                                           OAc      CN         CH.sub.3                                                                            H    u   u   s                               ##STR186##                                                                           OAc      CH.sub.2 OAc                                                                             H     OH   u   u   s                               ##STR187##                                                                           Br                                                                                      ##STR188##                                                                              H     --   u   s   u                               ##STR189##                                                                           OAc      CHCH.sub.2 H     --   u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 147 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR190##                                                                     R.sub.1    R.sub.2     R.sub.3                                                                             R.sub.4                                                                             b   c                                    ______________________________________                                         ##STR191##                                                                            CH.sub.2    H       --    s   u                                       ##STR192##                                                                            CH.sub.2 OAc                                                                              H       --    s   u                                       ##STR193##                                                                            CN          H       --    s   u                                       ##STR194##                                                                            CONH.sub.2  H       --    s   u                                       ##STR195##                                                                            CH.sub.2    CH.sub.3                                                                              H     u   s                                       ##STR196##                                                                            CH.sub.2    CH.sub.3                                                                              --    s   u                                       ##STR197##                                                                             ##STR198## CH.sub.3                                                                              H     u   s                                       ##STR199##                                                                            CH.sub.2 Cl H       --    s   u                                       ##STR200##                                                                             ##STR201## H       --    s   u                                        NH.sub.2                                                                              ##STR202## H       --    s   u                                      ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1482S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5,5-ethylenedithio-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) and ethanedithiol (0.25 ml.) is treated with boron trifluorideetherate (0.25 ml.) at room temperature. After standing for 24 hours,the excess ethanedithiol is removed in vacuo and the residue is treatedwith 0.1N sodium hydroxide and ether containing a trace of pyridine. Thetwo phases are separated, the ethereal layer is washed with saturatedsalt solution, dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5,5-ethylenedithio-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 148 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

    ______________________________________                                         ##STR203##                                                                     R.sub.1   R.sub.2  R.sub.3  R.sub.4                                                                              R.sub.5                                                                           a   b   c                            ______________________________________                                        OH                                                                                     ##STR204##                                                                             ##STR205##                                                                              H      --  u   s   u                               ##STR206##                                                                           OH       CH.sub.2 OH                                                                              H      H   s   s   s                               ##STR207##                                                                           OH       CH.sub.2 OAc                                                                             CH.sub.3                                                                             --  u   s   u                               ##STR208##                                                                           OH       CH.sub.2 OAc                                                                             CH.sub.2                                                                             H   u   s   s                               ##STR209##                                                                           OAc      CO.sub.2 H H      --  u   s   u                               ##STR210##                                                                           OAc      CO.sub.2 H CH.sub.3                                                                             H   u   u   s                               ##STR211##                                                                           OAc      CO.sub.2 C.sub.2 H.sub.5                                                                 CH.sub.3                                                                             H   u   u   s                               ##STR212##                                                                            ##STR213##                                                                            CONH.sub.2 H      --  u   s   u                                N(CH.sub.3).sub.2                                                                   OAc                                                                                     ##STR214##                                                                              H      --  u   s   u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 148 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR215##                                                                       R.sub.1 R.sub.2      R.sub.3                                                                            R.sub.4 b   c                                   ______________________________________                                         ##STR216##                                                                           CH.sub.3     H      --      s   u                                      ##STR217##                                                                           CH.sub.2 OAc H      --      s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

Example 1492S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5,5-ethylenethiooxy-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) in dioxane (1.0 ml.) is treated with β-mercaptoethanol (400mg.) followed by the addition of freshly fused zinc chloride (500 mg.)and anhydrous sodium acetate (500 mg.). The solution is initially cooledin ice and then allowed to warm to room temperature. After 24 hours, thereaction mixture is diluted with water (25 ml.) and extracted withchloroform. The organic extract is then washed with saturated saltsolution, dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl5,5-ethylenethiooxy-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 149 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR218##                                                                     R.sub.1 R.sub.2  R.sub.3 R.sub.4                                                                             R.sub.5                                                                           a     b   c                              ______________________________________                                         ##STR219##                                                                         OAc      CH.sub.2 OH                                                                             H     --  u     s   u                                 ##STR220##                                                                         OAc                                                                                     ##STR221##                                                                             H     --  u     s   u                                ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compound is prepared according to the procedure of Example149 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR222##                                                                       R.sub.1 R.sub.2     R.sub.3                                                                            R.sub.4 b   c                                    ______________________________________                                         ##STR223##                                                                           CH.sub.2 OAc                                                                              H      --      s   u                                      ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1502S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane

Following the procedure of Example 74, but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepanefor2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,there is obtained2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 150 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR224##                                                                     R.sub.1   R.sub.2  R.sub.3 R.sub.4                                                                             R.sub.5                                                                            a   b    c                            ______________________________________                                        (OCH.sub.3).sub.2                                                                     OAc      CH.sub.2 OAc                                                                            CH.sub.3                                                                            H    s   s    s                              (OCH.sub.3).sub.2                                                                     OAc      CH.sub.2 OAc                                                                            CH.sub.3                                                                            H    u   s    s                              (OCH.sub.3).sub.2                                                                     OAc      CONH.sub.2                                                                              CH.sub.3                                                                            H    u   u    s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 150 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

    ______________________________________                                         ##STR225##                                                                     R.sub.1    R.sub.2      R.sub.3                                                                            R.sub.4 b   c                                  ______________________________________                                        OAc      CH(OCH.sub.3).sub.2                                                                        H      --      s   u                                    (OCH.sub.3).sub.2                                                                      CH.sub.2     H      OH      u   s                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1512S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5,5-di-(ethylthio)-7-nonenyl]-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) in ethyl mercaptan (17.5 ml.) is treated with anhydrous sodiumsulfate (880 mg.) and freshly fused zine chloride (440 mg.). Thereaction flask is stoppered and kept in the cold for 72 hours. Theexcess mercaptan is removed in vacuo and the residue is treated with0.1N sodium hydroxide and ethyl ether containing a trace of pyridine.The phases are separated and the organic layer is washed with saturatedsalt solution, dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5,5-di-(ethylthio)-7-nonenyl]-oxepane.

The following compound is prepared according to the procedure of Example151 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR226##                                                                     R.sub.1   R.sub.2   R.sub.3 R.sub.4                                                                            R.sub.5                                                                           a    b   c                             ______________________________________                                         ##STR227##                                                                            ##STR228##                                                                             CH.sub.2 OAc                                                                            H    --  u    s   u                               ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 151 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR229##                                                                       R.sub.1   R.sub.2       R.sub.3                                                                            R.sub.4                                                                             b   c                                  ______________________________________                                        (SC.sub.2 H.sub.5).sub.2                                                                CH(SC.sub.2 H.sub.5).sub.2                                                                  H      --    s   u                                    CH.sub.2  CH(SC.sub.2 H.sub.5).sub.2                                                                  H      --    s   u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1522S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(spiro-2-thiazolidine)-7-nonenyl]-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg.) in anhydrous benzene (20 ml.) is treated with2-mercaptoethylamine (165 mg.) and p-toluenesulfonic acid (5 mg.) undera Dean-Stark trap at reflux in a nitrogen atmosphere for 48 houars. Thereaction mixture is washed with cold, saturated salt solution and theorganic layer dried and evaporated to give2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-[4,8-dimethyl-5-(spiro-2-thiazolidine)-7-nonenyl]-oxepane.

The following compounds are prepared according to the procedure ofExample 152 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR230##                                                                     R.sub.1  R.sub.2 R.sub.3   R.sub.4                                                                             R.sub.5                                                                            a   b    c                            ______________________________________                                        OH     OAc                                                                                    ##STR231## H     --   u   s    u                               ##STR232##                                                                          OAc     CH.sub.2 OAc                                                                              CH.sub.3                                                                            H    s   s    s                               ##STR233##                                                                          OAc     CH.sub.2 OAc                                                                              H     H    s   u    s                               ##STR234##                                                                          OAc     CO.sub.2 CH.sub.3                                                                         H     --   u   s    u                               ##STR235##                                                                          OAc     CN          H     --   u   s    u                                CH.sub.2                                                                           OAc                                                                                    ##STR236## H     --   u   s    u                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 152 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR237##                                                                       R.sub.1   R.sub.2     R.sub.3                                                                            R.sub.4                                                                              b   c                                   ______________________________________                                         ##STR238##                                                                             CO.sub.2 C.sub.4 H.sub.9                                                                  H      --     s   u                                      ##STR239##                                                                              ##STR240## H      --     s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1532S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepan-3-ol

2S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(407 mg.) is dissolved in tetrahydrofuran (8 ml.). The solution iscooled to 31 78° under nitrogen and treated slowly with an excess ofmethyllithium (3 ml., 1.6M in ether). The reaction mixture is kept at3178° for 10 minutes and then slowly warmed to room temperature byremoving the cooling bath. The mixture is then treated with ether (100ml.) and saturated NH₄ Cl solution (50 ml.). The organic layer is washedwith water (50 ml.), dried (MgSO₄) and evaporated in vacuo to give2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepan-3-ol(410 mg.).

IR (neat) μ:2.87; NMR_(TMS) ^(CDCl).sbsp.3 δ: ##STR241##

Similarly, by substituting other organolithium or organomagnesiumhalides for methyllithium in the procedure of Example 153, thecorresponding alcohols are formed. Thus, n-butyllithium, ethyllithium,allyl magnesium bromide and 1-propenyl magnesium bromide afford then-butyl carbinol, ethyl carbinol, allyl carbinol and 1-propenylcarbinol, respectively.

The following compounds are prepared by the procedure of Example 153 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oland employing the appropriate organometallic reagent.

    ______________________________________                                         ##STR242##                                                                     R.sub.1      R.sub.2 R.sub.3  R.sub.4                                                                             R.sub.5                                                                           abc                                 ______________________________________                                         ##STR243##                                                                              OH      CH.sub.2 OH                                                                              H     --  usu                                    ##STR244##                                                                               ##STR245##                                                                           CH.sub.2 OH                                                                              H     --  usu                                     OH       OH                                                                                     ##STR246##                                                                              H     --  usu                                    ##STR247##                                                                              OH      CH.sub.2 OH                                                                              H     --  ssu                                    ##STR248##                                                                              OH      CH.sub.2 OH                                                                              CH.sub.2                                                                            H   uss                                    ##STR249##                                                                              OH      CH.sub.2 OH                                                                              H     H   sus                                    ##STR250##                                                                              OH      CH.sub.2 OH                                                                              H     H   sss                                    ##STR251##                                                                              OH      CH.sub.2 OH                                                                              CH.sub.3                                                                            --  uss                                   ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the procedure of Example 153 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oland employing the appropriate organometallic reagent.

    ______________________________________                                         ##STR252##                                                                     R.sub.1       R.sub.2    R.sub.3                                                                             R.sub.4                                                                             b   c                                  ______________________________________                                         ##STR253## CH.sub.2   H       --    s   u                                     ##STR254##                                                                                ##STR255##                                                                              H       --    s   u                                     ##STR256## CH.sub.2   CH.sub.3                                                                              --    s   u                                     ##STR257## CH.sub.2   CH.sub.3                                                                              H     u   s                                     ##STR258## CH.sub.2 OH                                                                              CH.sub.3                                                                              --    s   u                                     ##STR259##                                                                                ##STR260##                                                                              H       --    s   u                                      CH.sub.2                                                                                 ##STR261##                                                                              H       --    s   u                                     ##STR262## CH.sub.2   H       --    s   u                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1542S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-ethynyl-5-hydroxy-7-nonenyl)-oxepan-3-ol

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(600 mg.) in anhydrous dioxane (10 ml.) is added at room temperature toa stirred mixture of lithium acetylide ethylenediamine complex (2.6 g.)in anhydrous dioxane (30 ml.). A stream of acetylene is passed throughthis stirred mixture for 24 hours. The reaction mixture is then treatedwith a saturated ammonium chloride solution (50 ml.) and ether (200ml.). The organic phase is dried and evaporated in vacuo to give a brownoily residue which is plate chromatographed on silica gel, using ethylacetate-cyclohexane (1:1) as the developing solvent. The most polar bandis eluted with isopropanol-chloroform (1:1) to afford2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-ethynyl-5-hydroxy-7-nonenyl)-oxepan-3-ol(246 mg.).

IR (neat) μ: 2.93, 3.0, 4.23;

NMR_(TMS) ^(CDCl).sbsp.3 δ: ##STR263##

The following compounds are prepared by the procedure of Example 154 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR264##                                                                     R.sub.1   R.sub.2  R.sub.3 R.sub.4                                                                             R.sub.5                                                                            a   b    c                            ______________________________________                                         ##STR265##                                                                           OH       CH.sub.2 OH                                                                             CH.sub.3                                                                            H    s   s    s                               ##STR266##                                                                           OH       CH.sub.2 OH                                                                             CH.sub.3                                                                            H    s   u    s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compound is prepared according to the procedure of Example154 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR267##                                                                       R.sub.1   R.sub.2     R.sub.3                                                                            R.sub.4                                                                              b   c                                   ______________________________________                                         ##STR268##                                                                             CH.sub.2    H      --     s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1552S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-ethenyl-5-hydroxy-7-nonenyl)-oxepan-3-ol

Treatment of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olwith an excess of vinyl magnesium bromide as in Example 154 affords2S,3R-6-(2-hydroxyethylidene)-2-(4,8-dimethyl-5-ethenyl-5-hydroxy-7-nonenyl)-oxepan-3-ol.

The following compounds are prepared according to the method of Example155 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR269##                                                                     R.sub.1    R.sub.2    R.sub.3 R.sub.4                                                                            R.sub.5                                                                           a   b   c                            ______________________________________                                        OH                                                                                      ##STR270##                                                                              CH.sub.2 OH                                                                             H    --  u   s   u                               ##STR271##                                                                            OH         CH.sub.2 OH                                                                             H    H   u   s   s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 155 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3ol.

    ______________________________________                                         ##STR272##                                                                       R.sub.1    R.sub.2    R.sub.3                                                                            R.sub.4                                                                              b   c                                   ______________________________________                                         ##STR273##                                                                              CH.sub.2   H      --     s   u                                      ##STR274##                                                                              CH.sub.3   H      --     s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1562S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-phenyl-7-nonenyl)-oxepan-3-ol

Treatment of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olwith phenyllithium as in Example 154 affords2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-phenyl-7-nonenyl)-oxepan-3-ol.

The following compounds are prepared according to the procedure ofExample 156 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR275##                                                                     R.sub.1  R.sub.2  R.sub.3   R.sub.4                                                                              R.sub.5                                                                           a   b   c                            ______________________________________                                        OH                                                                                    ##STR276##                                                                             ##STR277## H      --  u   s   u                                OH   OH                                                                                      ##STR278## H      --  u   s   u                               ##STR279##                                                                          OH       CH.sub.2 OH CH.sub.3                                                                             H   u   s   s                               ##STR280##                                                                          OH       CH.sub.2 OH CH.sub.3                                                                             --  s   s   u                               ##STR281##                                                                          OH       CH.sub.2 OH CH.sub.2                                                                             H   s   s   s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared by the procedure of Example 156 bysubstituting an equivalent amount of the appropriate starting materialfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR282##                                                                       R.sub.1   R.sub.2     R.sub.3                                                                            R.sub.4                                                                              b   c                                   ______________________________________                                         ##STR283##                                                                             CH.sub.3    H      --     s   u                                      ##STR284##                                                                              ##STR285## H      --     s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1572S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(5-benzyl-4,8-dimethyl-5hydroxy-7-nonenyl)-oxepan-3-ol

Treatment of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-olwith 4 eq. of benzyl magnesium bromide (freshly prepared from benzylbromide and magnesium in ether) as in Example 155 affords2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-benzyl-4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol.

The following compounds are prepared according to the procedure ofExample 157 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR286##                                                                     R.sub.1     R.sub.2  R.sub.3 R.sub.4                                                                             R.sub.5                                                                           a   b   c                            ______________________________________                                         ##STR287##                                                                             OH       CH.sub.2 OH                                                                             CH.sub.3                                                                            H   u   u   s                               ##STR288##                                                                             OH       CH.sub.2 OH                                                                             H     H   u   u   s                              ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 157 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR289##                                                                       R.sub.1    R.sub.2   R.sub.3                                                                            R.sub.4 b   c                                   ______________________________________                                         ##STR290##                                                                              CH.sub.2  H      --      s   u                                      ##STR291##                                                                              CH.sub.2  H      OH      u   s                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 157A2S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propynyl-7-nonenyl)-oxepan-3-ol

Lithium propynide is generated by slow addition of n-butyllithium (4mmole) to a solution of propyne (1 ml.) in tetrahydrofuran (15 ml.) at-78° under argon. To this reagent is added2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(330 mg.) in tetrahydrofuran (1 ml.) at room temperature and theresulting mixture is stirred for 5 hours. The mixture is treated withether (50 ml.) and saturated ammonium chloride solution (30 ml.). Theorganic phase is dried and evaporated in vacuo to afford2S,3R-6(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propynyl-7-nonenyl)-oxepan-3-ol.

Similarly by substituting other 1-alkynes for propyne in the procedureof Example 157A, the corresponding alcohols are formed. Thus, lithiumpentynide and lithium hexynide afford the 1-pentynyl carbinol and1-hexynyl carbinol respectively.

EXAMPLE 1582S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methylene-7-nonenyl)-3-trimethylsiloxyoxepane

To a mixture of (methyl)-triphenylphosphonium iodide (406 mg.) andtetrahydrofuran (10 ml) is added n-butyllithium at -20° under argon;2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane(504 mg.) is added to this reagent and the mixture is stirred for 30minutes. The resulting mixture is allowed to warm to room temperatureand is stirred for another 30 minutes. The mixture is then poured intobuffer (pH=7, 30 ml.). The resulting mixture is then extracted withether. The combined organic phase is dried and evaporated to afford2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methylene-7-nonenyl)-3-trimethylsiloxyoxepane.

The following compounds are prepared according to the procedure ofExample 158 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane.

    ______________________________________                                         ##STR292##                                                                     R.sub.1 R.sub.2    R.sub.3    R.sub.4                                                                             R.sub.5                                                                             a b c                             ______________________________________                                        CH.sub.2                                                                            OH         CH.sub.2 OH  H     --    usu                                 CH.sub.2                                                                            CH.sub.2   CH.sub.2 OH  H     --    usu                                 OH    CH.sub.2   CHCH.sub.2   H     --    usu                                 OH    CH.sub.2   CH.sub.2 OH  H     --    usu                                 OH    OAc        CHCH.sub.2   H     --    usu                                 CH.sub.2                                                                            OH         CH.sub.2 OH  CH.sub.3                                                                            H     uu s                                CH.sub.2                                                                            OH         CH.sub.2 OH  H     H     sss                                 CH.sub.2                                                                            OH         CH.sub.2 OH  CH.sub.3                                                                            H     sss                                 CH.sub.2                                                                            OH         CH.sub.2 OH  H     H     uss                                 CH.sub.2                                                                            OH         CH.sub.2 OH  CH.sub.3                                                                            H     uss                                 CH.sub.2                                                                            OH         CH.sub.2 OH  CH.sub.3                                                                            --    ssu                                 CH.sub.2                                                                            OAc        CO.sub.2 CH.sub.3                                                                          H     --    usu                                 CH.sub.2                                                                            CH.sub.2   CO.sub.2 C.sub.2 H.sub.5                                                                   CH.sub.3                                                                            H     uu s                                CH.sub.2                                                                            CH.sub.2   CO.sub.2 H   H     --    usu                                 OH    CH.sub.2   CONH.sub.2   H     --    usu                                 CH.sub.2                                                                            OAc        CONH.sub.2   CH.sub.3                                                                            H     uu s                                CH.sub.2                                                                            OAc        CN           CH.sub.3                                                                            H     su s                                CH.sub.2                                                                            OCOC.sub.6 H.sub.5                                                                       CH.sub.2 OCOC.sub.6 H.sub.5                                                                H     OH    uu s                                 ##STR293##                                                                         CH.sub.2   CHCH.sub.2   H     --    usu                                 ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 158 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane.

    ______________________________________                                         ##STR294##                                                                       R.sub.1  R.sub.2    R.sub.3                                                                             R.sub.4 b   c                                   ______________________________________                                        CH.sub.2 CH.sub.2   H       --      s   u                                     CH.sub.2 CH.sub.2 OH                                                                              H       --      s   u                                     OAc      CHCH.sub.2 H       --      s   u                                     CH.sub.2 CO.sub.2 H H       --      s   u                                     CH.sub.2 CONH.sub.2 H       --      s   u                                     CH.sub.2 CH.sub.2   CH.sub.3                                                                              H       u   s                                     CH.sub.2 CH.sub.2 OH                                                                              CH.sub.3                                                                              H       u   s                                     CH.sub.2 CH.sub.2 OAc                                                                             H       --      s   u                                      ##STR295##                                                                            CHCH.sub.2 H       --      s   u                                       CH.sub.2                                                                             CHCH.sub.2 H       --      s   u                                     ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1592S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-ethylidene-7-nonenyl)-3-trimethylsiloxyoxepane

Following the procedure of Example 158 but substituting an equivalentamount of (ethyl)-triphenylphosphonium iodide for(methyl)-triphenylphosphonium iodide,2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-ethylidene-7-nonenyl)-3-trimethylsiloxyoxepaneis obtained.

Similarly by substituting other phosphonium halides for(ethyl)-triphenylphosphonium iodide in the procedure of Example 159, thecorresponding alkylidene derivatives are formed. Thus,(benzyl)-triphenylphosphonium chloride and (butyl)-triphenylphosphoniumbromide afford the benzylidene and butylidene derivatives respectively.

The following compounds are prepared according to the procedure ofExample 159 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepaneand employing the appropriate phosphonium halide.

    __________________________________________________________________________     ##STR296##                                                                   R.sub.1   R.sub.2                                                                              R.sub.3   R.sub.4                                                                           R.sub.5                                                                         a b c                                        __________________________________________________________________________    OH        OAc    CHCHCH.sub.3                                                                            H   --                                                                              u s u                                        CHCH.sub.3                                                                              OH     CH.sub.2 OH                                                                             H   --                                                                              s s s                                        CHC.sub.2 H.sub.5                                                                       OH     CH.sub.2 OH                                                                             CH.sub.3                                                                          H s u s                                        CHCH.sub.3                                                                              OH     CH.sub.2 OH                                                                             H   H u u s                                        CHC.sub.6 H.sub.5                                                                       OH     CH.sub.2 OH                                                                             CH.sub.3                                                                          --                                                                              u s u                                        CHCH.sub.3                                                                              OH     CH.sub. 2 OH                                                                            CH.sub.2                                                                          H u s s                                        CHC.sub.6 H.sub.5                                                                       OH     CH.sub.2 OH                                                                             H   H s u s                                        CHCH.sub.3                                                                              OH     CH.sub.2 OH                                                                             CH.sub.2                                                                          H s s s                                        CHCHCH.sub.2                                                                            OH     CH.sub.2 OH                                                                             H   --                                                                              u s u                                        CHCHCH.sub.2                                                                            OH     CH.sub.2 OH                                                                             CH.sub.3                                                                          H u u s                                        CHC.sub.6 H.sub.5                                                                       OAc    CO.sub.2 CH.sub.3                                                                       H   --                                                                              u s u                                        CHCH.sub.3                                                                              CHCH.sub.3                                                                           CO.sub.2 H                                                                              CH.sub.3                                                                          H s u s                                        CHC.sub.6 H.sub.5                                                                       OAc    CN        H   --                                                                              u s u                                        CHCH.sub.3                                                                              CHCH.sub.3                                                                           CN        CH.sub.3                                                                          H u u s                                         ##STR297##                                                                             CHCH.sub.3                                                                           CHCHCH.sub.3                                                                            H   H s s s                                        CHC.sub.6 H.sub.5                                                                       CHC.sub.6 H.sub.5                                                                    CH.sub.2 OAc                                                                            H   --                                                                              u s u                                        OAc       OAc    CHCHC.sub.2 H.sub.5                                                                     H   --                                                                              u s u                                        __________________________________________________________________________     u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 159 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane.

    ______________________________________                                         ##STR298##                                                                     R.sub.1       R.sub.2      R.sub.3                                                                             R.sub.4                                                                             b   c                                ______________________________________                                        CHCH.sub.3  CH.sub.3     H       --    s   u                                  CHC.sub.6 H.sub.5                                                                         CO.sub.2 H   H       --    s   u                                  CHCHCH.sub.2                                                                              CN           H       --    s   u                                  CHCH.sub.3  CO.sub.2 CH.sub.3                                                                          H       --    s   u                                  CHCH.sub.3  CH.sub.2     CH.sub.3                                                                              --    s   u                                  CHCH.sub.3  CH.sub.2     H       OH    u   s                                  CHC.sub.6 H.sub.5                                                                         CONHC.sub.2 H.sub.5                                                                        H       --    s   u                                   ##STR299## CHCHC.sub.6 H.sub.5                                                                        H       --    s   u                                    (OCH.sub.3).sub.2                                                                       CHCHC.sub.6 H.sub.5                                                                        H       --    s   u                                  ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1602S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3-trimethylsiloxyoxepane

Following the procedure of Example 18 but substituting an equivalentamount of2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepanefor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3-trimethylsiloxyoxepaneis obtained.

EXAMPLE 1612S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-toluenesulfonyloxy-7-nonenyl)-3-trimethylsiloxyoxepane

To a mixture of2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3-trimethylsiloxyoxepane(506 mg), pyridine (1 ml) and ether (20 ml) is added p-toluenesulfonylchloride (195 mg) at 0° under argon. The mixture is stirred for 1 hourand then treated with ether (30 ml) and water (30 ml). The organic layeris washed with saturated cupric sulfate and the organic phase is thendried and evaporated to afford2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-toluenesulfonyloxy-7-nonenyl)-3-trimethylsiloxyoxepane.

EXAMPLE 1622S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,5,8-trimethyl-7-nonenyl)-3-trimethylsiloxyoxepane

Lithium dimethyl copper is generated from cuprous iodide (190 mg) andmethyl lithium (2 mmole) in ether (10 ml) at 0° under argon. A solutionof2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-toluenesulfonyloxy-7-nonenyl)-3-trimethylsiloxyoxepane(300 mg) in ether (5 ml) is added slowly to this reagent at -20° underargon. The mixture is allowed to warm to room temperature and stirredfor 5 hours. The mixture is then poured into saturated ammonium chloridesolution (30 ml) at 0° and then quickly extracted with ether (100 ml).The organic layer is dried and evaporated in vacuo to afford2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,5,8-trimethyl-7-nonenyl)-3-trimethylsiloxyoxepane.

EXAMPLE 1632S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-cyano-4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

To a mixture of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(422 mg), sodium cyanide (300 mg), tetrahydrofuran (9 ml), and water (1ml) is added concentrated hydrochloric acid (1 ml) at -20°. The mixtureis stirred overnight and treated with ether (30 ml) and water (10 ml).The organic layer is dried and evaporated to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-cyano-4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane.

The following compounds are prepared according to the procedure ofExample 163 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR300##                                                                     R.sub.1  R.sub.2  R.sub.3    R.sub.4                                                                             R.sub.5                                                                             ab c                               ______________________________________                                         ##STR301##                                                                          OH       CH.sub.2 OH  H     --    u su                                  ##STR302##                                                                           ##STR303##                                                                            CH.sub.2 OH  H     --    u su                                  ##STR304##                                                                          OCH.sub.3                                                                              CH.sub.2 OCH.sub.3                                                                         H     --    u su                                   OH                                                                                  ##STR305##                                                                            CH.sub.2 OH  H     --    u su                                 OH     OAc                                                                                     ##STR306##  H     --    u su                                   Br   OAc                                                                                     ##STR307##  H     --    u su                                  ##STR308##                                                                           ##STR309##                                                                             ##STR310##  H     --    u su                                  ##STR311##                                                                          Cl       CH.sub.2 Cl  CH.sub.3                                                                            H     u u s                                 ##STR312##                                                                          Cl       CH.sub.2 Cl  H     H     sss                                   ##STR313##                                                                          Br       CH.sub.2 Br  H     --    ssu                                   ##STR314##                                                                          OAc      CH.sub.2 OAc H     H     u ss                                  ##STR315##                                                                          Cl       CH.sub.2 Cl  CH.sub.3                                                                            H     su s                                  ##STR316##                                                                          OAc      CH.sub.2 OAc CH.sub.3                                                                            H     u ss                                  ##STR317##                                                                          OAc      CH.sub. 2 OAc                                                                              H     H     u u s                                 ##STR318##                                                                          Br       CH.sub.2 Br  CH.sub.3                                                                            --    u su                                  ##STR319##                                                                          Br       CH.sub.2 Br  CH.sub.2                                                                            H     u ss                                  ##STR320##                                                                          OAc      CH.sub.2 OAc H     H     su s                                  ##STR321##                                                                          Br       CH.sub.2 Br  CH.sub.3                                                                            --    ssu                                   ##STR322##                                                                          OAc      CH.sub.2 OAc CH.sub.2                                                                            --    ssu                                   ##STR323##                                                                          OAc      CO.sub.2 C.sub.2 H.sub.5                                                                   H     --    u su                                  ##STR324##                                                                          OAc      CO.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                          CH.sub.3                                                                            H     u u s                                 ##STR325##                                                                          OAc      CO.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                          H     H     u u s                                 ##STR326##                                                                          OAc      CO.sub.2 CH.sub.3                                                                          H     --    u su                                  ##STR327##                                                                          OAc      CO.sub.2 C.sub.2 H.sub.5                                                                   CH.sub.3                                                                            H     u u s                                 ##STR328##                                                                          Br       CO.sub.2 CH.sub.3                                                                          H     --    u su                                  ##STR329##                                                                          Br       CO.sub.2 H   H     --    u su                                  ##STR330##                                                                          Cl       CONH.sub.2   H     --    u su                                  ##STR331##                                                                          OAc      CONH.sub.2   CH.sub.3                                                                            H     u u s                                 ##STR332##                                                                          OAc      CN           --    --    u su                                  ##STR333##                                                                          OAc      CN           CH.sub.3                                                                            H     u u s                                 ##STR334##                                                                          Br       CH.sub.2 Br  H     OH    u u s                                 ##STR335##                                                                          OAc                                                                                     ##STR336##  H     --    u su                                  ##STR337##                                                                          OAc                                                                                     ##STR338##  H     --    u su                                   CH.sub.2                                                                           OAc                                                                                     ##STR339##  H     --    u su                                   CH.sub.2                                                                            ##STR340##                                                                            CH.sub.2 OAc H     --    u su                                  ##STR341##                                                                          OAc                                                                                     ##STR342##  H     --    u su                                  ##STR343##                                                                          OAc                                                                                     ##STR344##  H     --    u su                                 ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 163 by substituting an equivalent amount of the appropriatestarting material for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR345##                                                                       R.sub.1   R.sub.2      R.sub.3                                                                              R.sub.4                                                                            b    c                                 ______________________________________                                         ##STR346##                                                                             CH.sub.2     H        --   s    u                                    ##STR347##                                                                             CH.sub.3     H        --   s    u                                    ##STR348##                                                                             CH.sub.2 OH  H        --   s    u                                    ##STR349##                                                                              ##STR350##  H        --   s    u                                    ##STR351##                                                                             CO.sub.2 H   H        --   s    u                                    ##STR352##                                                                             C N          H        --   s    u                                    ##STR353##                                                                             CH.sub.2 Br  H        --   s    u                                    ##STR354##                                                                             CO.sub.2 C.sub.4 H.sub.9                                                                   H        --   s    u                                    ##STR355##                                                                             CONH.sub.2   H        --   s    u                                    ##STR356##                                                                             CH.sub.2     CH.sub.3 H    u    s                                    ##STR357##                                                                             CH.sub.2     CH.sub.3 --   s    u                                     Cl                                                                                     ##STR358##  CH.sub.3 H    u    s                                    ##STR359##                                                                             CONH.sub.2   H        H    u    s                                    ##STR360##                                                                             CON(CH.sub.3).sub.2                                                                        H        --   s    u                                    ##STR361##                                                                              ##STR362##  H        --   s    u                                    ##STR363##                                                                              ##STR364##  H        --   s    u                                     CH.sub.2                                                                               ##STR365##  H        --   s    u                                    ##STR366##                                                                             CH.sub.2 OAc H        --   s    u                                    ##STR367##                                                                              ##STR368##  H        --   s    u                                    ##STR369##                                                                              ##STR370##  H        --   s    u                                   ______________________________________                                    

EXAMPLE 1642S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-5,7-nonadienyl)-oxepane

A mixture of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(430 mg), p-toluenesulfonic acid (2 mg) and isopropenyl acetate (10 ml)is refluxed under nitrogen for 16 hours. The solvent is removed in vacuobelow 50° to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-5,7-nonadienyl)-oxepane.

EXAMPLE 1652S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-trimethylsiloxy-5,7-nonadienyl)-3-trimethylsiloxyoxepane

Lithium diisopropylamide is generated from diisopropylamine andn-butyllithium at -20° under argon in tetrahydrofuran (10 ml). Asolution of2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-trimethylsiloxyoxepane(452 mg) in tetrahydrofuran (5 ml) is added to this reagent and theresulting mixture is stirred for 10 minutes. An excess of trimethylsilylchloride (150 mg) is added to this mixture and the mixture is allowed towarm to room temperature. The mixture is filtered and the filtrate istreated with pentane (30 ml). The resulting mixture is filtered againand the filtrate is concentrated in vacuo to afford2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-trimethylsiloxy-5,7-nonadienyl)-3-trimethylsiloxyoxepane.

EXAMPLE 1662S,3R-6-(2-Trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methoxy-5,7-nonadienyl)-3-trimethylsiloxyoxepane

Following the procedure of Example 165 but substituting an equivalentamount of trimethyloxonium tetrafluoroborate for trimethylsilylchloride,2S,3R-6-(2-trimethylsiloxyethylidene)-2-methyl-2-(4,8-dimethyl-5-methoxy-5,7-nonadienyl)-3-trimethylsiloxyoxepaneis obtained.

EXAMPLE 1672S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-8-hydroperoxy-5-oxo-6-nonenyl)-oxepan-3-ol

A solution of2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(0.980 g) in methanol (70 ml) containing Rose Bengal saturated anionexchange resin (AG1X8, 2.5 g) is irradiated with a 300 W tungsten lampfor 92 hours while bubbling oxygen through it. The suspension is stirredbriskly while being cooled with a cold finger throughout the period ofirradiation. The resin is removed by filtration and washed withmethanol. The combined filtrate and washings are distilled in vacuobelow 40°. The residue is plate chromatographed on silica gel usingisopropanol-chloroform (1:9) as the developing solvent. The most polaruv quenching band is eluted with isopropanol-chloroform (1:1) to afford2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-8-hydroperoxy-5-oxo-6-nonenyl)-oxepan-3-ol(213 mg).

IR (neat): 2.92 (OH), 5.94, 6.02 (conjugated (C═O), 6.14 (C═C), 11.8(--O--OH); uv (EtOH): 222 nm (ε5140); NMR (CDCl₃, δ): 1.08 (d, J=6 Hz,˜3H, CH₃ --CH), 1.15 (s, 3H, CH₃ --C--O--C), 1.36 [s, ˜6H (CH₃)₂--C--O--OH], 3.50 (m, ˜1H, H--C--OH), 4.06 (s, ˜2H, --O--CH₂ --C═C),4.26 (d, J=6 Hz, ˜2H, C═CH--CH₂ --OH), ˜5.4 (m, C═CH--CH₂ --OH), 6.20(d, J=16 Hz, CH═CH--C═O), 6.83 (d, J=16 Hz, CH═C--C═O).

The following compounds are prepared according to the procedure ofExample 167 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR371##                                                                       R.sub.2 R.sub.3            R.sub.4                                                                            a                                         ______________________________________                                        OH      CH.sub.2 OH        H      s                                           OH      CH.sub.2 OH        CH.sub.3                                                                             u                                           OH      CH.sub.2 OH        CH.sub.3                                                                             s                                           O       CH.sub.2 OH        H      s                                           O       CH.sub.2 OH        CH.sub.3                                                                             u                                           O       CH.sub.2 OH        CH.sub.3                                                                             s                                           O       CO.sub.2 H         H      s                                           O       CO.sub.2 H         CH.sub.3                                                                             u                                           O       CO.sub.2 H         CH.sub.3                                                                             s                                           OAc     CO.sub.2 H         H      s                                           OAc     CO.sub.2 H         CH.sub.3                                                                             u                                           OAc     CO.sub.2 H         CH.sub.3                                                                             s                                           O       CO.sub.2 CH.sub.3  H      s                                           O       CO.sub.2 CH.sub.3  CH.sub.3                                                                             u                                           O       CO.sub.2 CH.sub.3  CH.sub.3                                                                             s                                           OAc     CO.sub.2 CH.sub.3  H      s                                           OAc     CO.sub.2 CH.sub.3  CH.sub.3                                                                             u                                           OAc     CO.sub.2 CH.sub.3  CH.sub.3                                                                             s                                           O       CO.sub.2 Na        H      s                                           O       CO.sub.2 Na        CH.sub.3                                                                             u                                           O       CO.sub.2 Na        CH.sub.3                                                                             s                                           O       CONHCH.sub.2C.sub.6 H.sub.5                                                                      H      s                                           O       CON(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                                            CH.sub.3                                                                             u                                           O       CONH.sub.2         CH.sub.3                                                                             s                                           OAc     CON(CH.sub.3).sub.2                                                                              H      s                                           OAc     CONHC.sub.4 H.sub.9                                                                              CH.sub.3                                                                             u                                           OAc     CONHCH.sub.3       CH.sub.3                                                                             s                                           O       CN                 H      s                                           O       CN                 CH.sub.3                                                                             u                                           O       CN                 CH.sub.3                                                                             s                                           OAc     CN                 H      s                                           OAc     CN                 CH.sub.3                                                                             u                                           OAc     CN                 CH.sub.3                                                                             s                                           O       CH.sub.2 OH        H      u                                           O       CO.sub.2 H         H      u                                           OAc     CO.sub.2 H         H      u                                           O       CO.sub.2 CH.sub.3  H      u                                           OAc     CO.sub.2 CH.sub.3  H      u                                           O       CO.sub.2 Na        H      u                                           O       CONH.sub.2         H      u                                           OAc     CON(CH.sub.3).sub.2                                                                              H      u                                           O       CN                 H      u                                           OAc     CN                 H      u                                           ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 167 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR372##                                                                           R.sub.2       R.sub.3                                                 ______________________________________                                        CH.sub.2          H                                                           CH.sub.2          CH.sub.3                                                    CH.sub.3          CH.sub.3                                                    CH.sub.3          H                                                           CH.sub.2 OH       CH.sub.3                                                    COOH              CH.sub.3                                                    COOCH.sub.3       CH.sub.3                                                    CN                CH.sub.3                                                    CONHCH.sub.2C.sub.6 H.sub.5                                                                     CH.sub.3                                                    COOH              H                                                           COOCH.sub.3       H                                                           CN                H                                                           CONH.sub.2        H                                                           ______________________________________                                    

EXAMPLE 1682S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-8-hydroxy-5-oxo-6-nonenyl)-oxepan-3-ol

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-8-hydroperoxy-5-oxo-6-nonenyl)-oxepan-3-ol(354 mg) in methanol (30 ml) is stirred overnight withtriphenylphosphine. Evaporation of the solvent in vacuo affords aresidue which is plate chromatographed on silica gel usingisopropanol-chloroform (1:9) as the eluting solvent. The major band iseluted with isopropanol to afford2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-8-hydroxy-5-oxo-6-nonenyl)-oxepan-3-ol(173 mg):

NMR (CDCl₃, δ): 1.07 (d, J=7 Hz, ˜3H, CH₃ --CH), 1.08 (s, 3H, CH₃--C--O--C), 1.35 [s, 6H, (CH₃)₂ --C--OH)], 2.50 (broad s, OH),##STR373## 4.05 (s, 2H, --OCHHD 2--C═C), 4.1 (d, J=7 Hz, ˜2H, C═CH--CHHD2OH), 5.36 (m, 1H, C═CH13 CH₂ OH), 6.26 (d, J=16 Hz, 1H, CH═CH13 C═O),and 6.85 (d, J=16 Hz, 1H, CH50 CH--C═O); IR0 (neat) μ: 2.95 (OH); 3.25(C═C), 5.95, 6.04 (C═C--C═O), 6.15 (C═C); uv (EtOH): 224 nm (ε=9420).

EXAMPLE 1692S-3-Methoxy-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

A solution of2S,3R-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one(350 mg) in methanol (10 ml) is treated with glacial acetic acid (0.1ml). The resulting solution is refluxed for 3 hours, cooled andevaporated in vacuo to afford2S-3-methoxy-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

Similarly by substituting other hydroxy compounds for methanol in theprocedure of Example 169, the corresponding bicyclic derivatives areformed. Thus, ethanol and a water: tetrahydrofuran mixture afford the3-ethoxy and 3-hydroxy derivative respectively.

EXAMPLE 1702S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-toluenesulfonylhydrazono-7-nonenyl)-oxepane

Following the procedure of Example 124 but substituting an equivalentamount of p-toluenesulfonylhydrazide forp-bromobenzenesulfonylhydrazide,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-toluenesulfonylhydrazono-7-nonenyl)-oxepaneis obtained.

EXAMPLE 1712S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-p-toluenesulfonylhydrazono-7-nonenyl)-oxepane(590 mg) in methanol (25 ml) is treated with sodium borohydride (825 mg)at reflux under nitrogen. After 18 hours, the resulting solution isevaporated in vacuo and the residue partitioned between ether and water.The organic phase is then washed with a saturated salt solution, driedand evaporated to afford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-7-nonenyl)-oxepane.

EXAMPLE 1722S,3R-6-[6,1'-Oxido-2'-(tetrahydropyran-2-yloxy)-ethyl]-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxo-7-nonyl)-3-(tetrahydropyran-2-yloxy)-oxepane

Following the procedure of Example 27 but substituting an equivalentamount of2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepaneand two equivalents of m-chloroperbenzoic acid, 2S,3R-6-[6,1'-oxido-2'-(tetrahydropyran-2-yloxy)-ethyl]-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxo-7-nonyl)-3-(tetrahydropyran-2-yloxy)-oxepaneis obtained.

EXAMPLE 1732S,3R-6Z-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane

A solution of2S,3R-6-[6,1'-oxido-2'-(tetrahydropyran-2-yloxy)-ethyl]-2-methyl-2-(4,8-dimethyl-7,8-oxido-5-oxo-7-nonyl)-3-(tetrahydropyran-2-yloxy)-oxepane(0.506 g) in purified tetrahydrofuran (10 ml) is treated with lithiumdiphenylphosphide (6.8 ml of 0.55M solution in tetrahydrofuran) for 20hours at room temperature under nitrogen. Acetic acid (0.056 g) is addedfollowed by methyl iodide (0.284 g) and the mixture is allowed to standfor 0.5 hours at room temperature. After aqueous work up, the organicphase is evaporated to afford2S,3R-6Z-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane.

EXAMPLE 1742S,3R-6Z-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 12 but substituting an equivalentamount of2S,3R-6Z-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-(3-(tetrahydropyran-2-yloxy)-oxepanefor2S-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-onethere is obtained2S,3R-6Z-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

The compound of Example 174 can be substituted for2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oland converted to all the corresponding derivatives covered under thegeneric formula for monocyclic compounds.

EXAMPLE 1752S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 74 but substituting an equivalentamount of2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olfor2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-6-(2-hydroxyethylidene)-2-methyl2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 1762S,3R-6-(2-Acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 3 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-olfor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 1172S-6-(2-Acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-one

Following the procedure of Example 4 but substituting an equivalentamount of2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-olfor2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S-6-(2-acetoxyethylidene)2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-oneis obtained.

EXAMPLE 1782S,3S-6-(2-Acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 18 but substituting an equivalentamount of2S-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-onefor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olaffords a mixture of2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-oland2S,3S-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-ol.The compounds are separated by chromatography.

EXAMPLE 1792S,3S-6-(2-Acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 78 but substituting an equivalentamount of2S,3S-6-(2-acetoxyethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepan-3-olfor 2S,3,3-dimethoxy-2-methyl-6-cyanomethylene-2-(5,5-dimthoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3S-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olis obtained.

EXAMPLE 1802S,3S-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 21 but substituting an equivalentamount of2S,3S-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olfor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepaneaffords2S,3S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol.

The compound of Example 180 can be substituted for 2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oland converted to all the corresponding derivatives covered under thegeneric formula for monocyclic compounds.

EXAMPLE 1812S,3R-3-Acetoxy-6-(2-fluoroethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(390 mg) in methylene chloride (15 ml) is treated withN-(2-chloro-1,1,2-trifluoroethyl)-diethylamine (1.0 g) and the resultingmixture stirred at room temperature. After 24 hours the methylenechloride and excess N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine areevaporated in vacuo to afford2S,3R-3-acetoxy-6-(2-fluoroethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

EXAMPLE 1822S,3R-3-Acetoxy-6-(2-iodoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane

Sodium iodide (165 mg) is added to methyl ethyl ketone (10 ml) and theresulting suspension is allowed to reflux for 1 hour. The solution iscooled to 50° and a solution of2S,3R-3-acetoxy-6-(2-bromoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane(454 mg) in methyl ethyl ketone (2 ml) is added and the resultingsuspension stirred at 50°. After 12 hours, the mixture is cooled,filtered and the filtrate evaporated in vacuo to give a residue which ispartitioned between ether and water. The organic phase is washed with10% sodium bisulfite, 5% sodium bicarbonate, water, dried and evaporatedto afford2S,3R-3-acetoxy-6-(2-iodoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane.

EXAMPLE 1832S,3R,6R-2-Methyl-6-carboxymethyl-2-(4,8-dimethyl-5-ethynyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 110 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-ethynyl-5-hydroxy-7-nonenyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-olaffords a residue which is plate chromatographed on silica gel, usingisopropanol-chloroform (1:12) as the eluting solvent. The major band iseluted with isopropanol-chloroform (2:1) to afford2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-ethynyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(252 mg).

NMR (CDCl₃ --D₂ O)δ: 0.98 and 1.03 [a pair of doublets, J=6 Hz, 3H,##STR374## 1.33 (s, 3H, --CHHD 3--C--O--), 1.65 and 1.77 [each s, each3H, (CHHD 3)₂ --C═CH], 2.38 (s, 1H, --C.tbd.CH, 2.60 (s, 2H, CHHD 2--CO₂H), 3.37 and 3.75 (each d, J=11 Hz, 2H, --C--CHHD 2--O--C), 3.88 (m, 1H,H13 C--O--C), 5.12-5.48 [m, 1H, (CH₃)₂ --C═CH; IR (neat) μ: 2.89 (OH),5.80 (COOH).

EXAMPLE 1842S,3R,6R-6-(2-Oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane

A solution of2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(611 mg) in ethyl acetate (300 ml) is hydrogenated in the presence of10% palladium on carbon (400 mg) at atmospheric pressure for 1 hour. Themixture is filtered through a pad of celite and the solvent isevaporated in vacuo to give an oily residue. The residue is platechromatographed on silica gel using ethyl acetate-hexane (1:3) as thedeveloping solvent. The major band is eluted with the same solventsystem to afford2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane(540 mg).

NMR (CDCl₃) δ: 0.8 [d, J=6 Hz, 6H, (CHHD 3)₂ --CH), 1.06 (d, J=7 Hz, 3H,CH--CHHD 3), 1.30 (s, 3H, O--C--CHHD 3), 2.58 (d, J=2 Hz, 2H, CHHD2--CHO), 3.29 and 3.73 (each d, J=11 Hz, 2H, ##STR375## 9.80 (t, J=2 Hz,1H, CH); IR (neat) μ 3.63 (C--H of CHO), 5.80 (HC═O), 5.82 (>C═O).

EXAMPLE 1852S,3R,6R-2-Methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane

A solution of silver nitrate (1.328 g ) in water (18 ml) is treated with10% sodium hydroxide solution (11 ml) under nitrogen. A 15% ammoniumhydroxide solution (12.8 ml) is added dropwise with stirring until theprecipitate disappears. To this reagent a solution of2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane(300 mg) in methanol (10 ml) is added and the resulting mixture isheated at 85° C. for 5 hours. The mixture is then treated with ice water(160 ml), ethyl acetate (80 ml) and acidified to pH 3-4 with 5%hydrochloric acid. The organic layer is dried and evaporated in vacuo togive an oily residue which is plate chromatographed on silica gel, usingisopropanol chloroform (1:11) with a few drops of acetic acid as theeluting solvent. The major band is eluted with isopropanolchloroform(1:1) to afford 2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane (167 mg).

NMR (CDCl₃) δ: 0.88 (d, J=6 Hz, 6H, (CHHD 3)₂ --CH--), 1.06 (d, J=7 Hz,3H, CH--CHHD 3), 1.30 (s, 3H, O--C--CHHD 3), 2.62 (s, 2H, CHHD 2--CO₂H), 3.36 and 3.78 (each d, J=11 Hz, ##STR376## 4.67-5.05 (broad s, 1H,COOH exchanged with D₂ O); IR (neat) μ: 5.75 (HO--C═O), 5.83 (>C═O).

EXAMPLE 1862S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane

A solution of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-ol(474 mg) in pyridine (6.0 ml) is treated with acetic anhydride (4.5 ml)at room temperature under nitrogen for 18 hrs. The pyridine is removedin vacuo and methanol is added to destroy excess acetic anhydride. Thesolvent is removed in vacuo and the residue (600 mg) is platechromatographed on silica gel, using ethyl acetate-cyclohexane as thedeveloping solvent. The major band is eluted with ethyl acetate toafford2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-acetoxy-4,8-dimethyl-7-nonenyl)-oxepane(390 mg).

IR (neat): 5.75μ, (C═O);

NMR (CDCl₃,δ): 0.89 (d, J=7 Hz, 3H, CH--CHHD 3), 1.15 (s, 3H,--O--C--CHHD 3), 1.60 and 1.66 (each s, each 3H, (CHHD 3)₂ --C═C); 2.03(s, 9H, O--CO--CHHD 3); 4.08 (s, 2H, --CHHD 2--O--C); 4.56 (d, J=7 Hz,2H, CHHD 2--OAc); 4.67-5.0 (m, 2H, CH13 OAc); 5.0-5.5 (m, 2H, C═CH13 CH₂OAc and (CH₃)₂ --C═CH.

EXAMPLE 1872S,3R,6R-2-Methyl-6-carboxymethyl-2-(4,8-dimethyl-8-hydroxy-5-oxo-6-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 110, but substituting2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol(660 mg) for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepan-3-olaffords a residue which is plate chromatographed on silica gel usingisopropanolchloroform-acetic acid (36:363:1) as the eluting solvent. Themost polar band is eluted with isopropanol to afford2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-8-hydroxy-5-oxo-6-nonenyl)-3,6-oxidooxepane(238 mg):

IR (CCl₄)μ: 2.8-3.3 broad (OH), 5.65 (shoulder), 5.82 (CO & COOH); NMR(CDCl₃)δ: 1.08 (d, J=7 Hz, 3H, CHHD 3--CH), ##STR377## 6.25 (d, J=16 Hz,1H, CH═CH13 C═O), 6.83 (d, J=16 Hz, 1H, CH50 CH--C═O) and 5.1 (broad s,1H, COOH.

EXAMPLE 1882S,3R-6-[2-Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-hydroxy-5-(3-tetrahydropyran-2'-yloxyprop-1-ynyl)-7-nonenyl]-3-(tetrahydropyran-2-yloxy)-oxepane

Following the procedure of Example 157A but substituting an equivalentamount of2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene)]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepanefor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-oland lithium 3-tetrahydropyran-2'-yloxyprop-1-ynide for lithiumpropynide,2S,3R-6-[2(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-hydroxy-5-(3-tetrahydropyran-2'-yloxyprop-1-ynyl)-7-nonenyl]-3-tetrahydropyran-2-yloxy)-oxepaneis obtained.

The following compound is prepared according to the procedure of Example188 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-6-[2-(tetrahydrofuran-2-yloxy)-ethylidene)]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane.

    ______________________________________                                         ##STR378##                                                                     R.sub.1          R.sub.2  R.sub.3                                                                              R.sub.4                                                                           a   b   c                              ______________________________________                                         ##STR379##    OTMS     OTMS     H   u   s   u                                ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compound is prepared according to the procedure of Example188 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene)]-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane.

    ______________________________________                                         ##STR380##                                                                     R.sub.1         R.sub.2     R.sub.3                                                                            R.sub.4                                                                            b   c                                 ______________________________________                                         ##STR381##   CH.sub.2 OTHP                                                                             H      --   s   u                                   ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1892S,3R-6-[2-(Tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propadienyl-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane

A suspension of lithium aluminum hydride (1 g.) in dry ether (20 ml.) isheated under reflux for 1 hr., cooled to room temperature and treateddropwise with stirring with a solution of2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-hydroxy-5-(3-tetrahydropyran-2'-yloxyprop-1-ynyl)-7-nonenyl]-3-(tetrahydropyran-2-yloxy)-oxepane(1 g.) in dry ether (20 ml.). The resulting suspension is heated underreflux for 2.5 hrs., and after cooling the reaction mixture, the excessmetal hydride is decomposed by the addition of acetone. A saturatedsolution of sodium sulfate and solid sodium sulfate are added toprecipitate the metal salts. The mixture is filtered and the solidswashed with methylene chloride. Removal of the solvent from the combinedfiltrate and washings affords2S,3R-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propadienyl-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepane.

The following compound is prepared according to the procedure of Example189 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-6-[2-tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-hydroxy-5-(3-tetrahydropyran-2'-yloxyprop-1-ynyl)-7-nonenyl]-3-tetrahydropyran-2-yloxy)-oxepane.

    ______________________________________                                         ##STR382##                                                                     R.sub.1      R.sub.2  R.sub.3                                                                              R.sub.4                                                                            R.sub.5                                                                           a   b   c                             ______________________________________                                         ##STR383##                                                                              OTMS     OTMS     H    --  u   s   u                               ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

The following compounds are prepared according to the procedure ofExample 189 by substituting an equivalent amount of the appropriatestarting material for2S,3R-6-[2-tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-hydroxy-5-(3-tetrahydropyran-2'-yloxyprop-1-ynyl)-7-nonenyl]-3-tetrahydropyran-2-yloxy)-oxepane.

    ______________________________________                                         ##STR384##                                                                     R.sub.1      R.sub.2      R.sub.3                                                                            R.sub.4                                                                             b   c                                  ______________________________________                                         ##STR385##                                                                              CH.sub.2 OTHP                                                                              H      --    s   u                                     ##STR386##                                                                              CH.sub.2 OTHP                                                                              CH.sub.3                                                                             --    u   s                                    ______________________________________                                         u -- unsaturated                                                              s -- saturated                                                           

EXAMPLE 1902S,3R-6-(2-Hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propadienyl-7-nonenyl)-oxepan-3-ol

Following the procedure of Example 12 but substituting an equivalentamount of2S,3R-6-[2-tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propadienyl-7-nonenyl)-3-(tetrahydropyran-2-yloxy)-oxepanefor2S-6-[2-(tetrahydropyran-2-yloxy)-ethylidene]-2-methyl-2-[4,8-dimethyl-5-(tetrahydropyran-2-yloxy)-7-nonenyl]-oxepan-3-oneaffords2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-5-propadienyl-7-nonenyl)-oxepan-3-ol.

EXAMPLE 1912S,3R-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 2 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example191 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepan-3-ol.

    ______________________________________                                         ##STR387##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CHCCH.sub.2                                                        ______________________________________                                    

EXAMPLE 1922S,3R-3-Acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 6 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example192 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR388##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CHCCH.sub.2                                                        ______________________________________                                    

EXAMPLE 1932S,3R-3-Acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 7 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example193 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR389##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2C.sub.6 H.sub.5                                                       CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CHCCH.sub.2                                                        ______________________________________                                    

The following compounds are prepared according to the procedure ofExample 193 by substituting the appropriate starting material for2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR390##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CHCCH.sub.2                                                                   CH.sub.3                                                           ______________________________________                                    

EXAMPLE 1942S,3R-3-Acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 56 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example194 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR391##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                  ______________________________________                                    

The following compounds are prepared according to the method of Example194 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR392##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CH.sub.3                                                           ______________________________________                                    

EXAMPLE 1952S,3R-3-Acetoxy-2-methyl-6-carbmethoxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 60 but substituting an equivalentamount of2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-3-acetoxy-2-methyl-6-carbmethoxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example195 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR393##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                  ______________________________________                                    

The following compounds are prepared according to the method of Example195 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.##STR394##

EXAMPLE 1962S,3R-3-Acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane,sodium salt

Following the procedure of Example 64 but substituting an equivalentamount of2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane,sodium salt is obtained.

The following compounds are prepared according to the method of Example196 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneand the appropriate basic hydroxide.

    ______________________________________                                         ##STR395##                                                                           M            R                                                        ______________________________________                                        Na               CCH                                                          K                CHCH.sub.2                                                   NH.sub.4         C.sub.6 H.sub.5                                              K                CH.sub.2 C.sub.6 H.sub.5                                     Na               CH.sub.2CHCH.sub.2                                           NH.sub.4                                                                      n-C.sub.4 H.sub.9                                                             ______________________________________                                    

The following compounds are prepared according to the method of Example196 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR396##                                                                           M            R                                                        ______________________________________                                        NH.sub.4         CCH                                                          Na               CHCH.sub.2                                                   K                C.sub.6 H.sub.5                                              Na               CH.sub.2 C.sub.6 H.sub.5                                     K                CH.sub.2CHCH.sub.2                                           NH.sub.4                                                                      n-C.sub.4 H.sub.9                                                                              CH.sub.3                                                     ______________________________________                                    

EXAMPLE 1972S,3R-3-Acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 76 but substituting an equivalentamount of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example197 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR397##                                                                    ##STR398##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CH.sub.3                                                           ______________________________________                                    

EXAMPLE 1982S,3R-3-Acetoxy-2-methyl-6-cyanomethylene-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 77 but substituting an equivalentamount of2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylene]-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S-3,3-dimethoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,2S,3R-3-acetoxy-2-methyl-6-cyanomethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example198 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-6-[2-(hydroxyimino)-ethylidene]-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

    ______________________________________                                         ##STR399##                                                                    ##STR400##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CHCCH.sub.2                                                                   CH.sub.3                                                           ______________________________________                                    

EXAMPLE 1992S,3R-3-Acetoxy-2-methyl-6-chloroformyl-methylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane

Following the procedure of Example 65 but substituting an equivalentamount of2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example199 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR401##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2C.sub.6 H.sub.5                                                       CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                  ______________________________________                                    

The following compounds are prepared according to the method of Example199 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR402##                                                                                R                                                                ______________________________________                                                   CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2 C.sub.6 H.sub.5                                                      CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CH.sub.3                                                           ______________________________________                                    

EXAMPLE 2002S,3R-3-Acetoxy-2-methyl-6-carbamoylmethylene-2-(4,5,8-trimethyl-5-oxo-7-nonenyl)-oxepane

Following the procedure of Example 66 but substituting an equivalentamount of2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepanefor2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,2S,3R-3-acetoxy-2-methyl-6-carbamoylmethylene-2-(4,5,8-trimethyl-5-oxo-7-nonenyl)-oxepaneis obtained.

The following compounds are prepared according to the method of Example200 by substituting an equivalent amount of the appropriate startingmaterial for2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepane.

    ______________________________________                                         ##STR403##                                                                    ##STR404##                                                                               R                                                                 ______________________________________                                                  CCH                                                                           CHCH.sub.2                                                                    C.sub.6 H.sub.5                                                               CH.sub.2C.sub.6 H.sub.5                                                       CH.sub.2CHCH.sub.2                                                            n-C.sub.4 H.sub.9                                                             CH.sub.3                                                            ______________________________________                                    

EXAMPLE 2012S,3R,6S-6-Carboxy-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-3,6-oxidooxepane

To a mixture of2S,3R,6E-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol(234.8 mg, 0.66 mmole) and acetone (20 ml), Jones reagent (3 mmole) isadded slowly at 0° under nitrogen. The reaction mixture is kept at 0° C.for 10 min and then is treated with methanol (5 ml), ether (30 ml) andwater (15 ml). The organic phase is extracted with 10% sodiumbicarbonate (3×20 ml). The aqueous phase is combined and acidified at 0°to pH 2 to 3 with 10% hydrochloric acid. The mixture is extracted withmethylene chloride (2×125 ml), the extracts are dried (MgSO₄) andevaporated to afford2S,3R,6S-6-carboxy-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-3,6-oxidooxepane(150 mg, 68% yield).

IR (neat) μ: 2.78-4.00(br), 5.78 (s), 5.94 (s), 6.17 (s); NMR_(TMS)^(CDCl).sbsp.3 δ: 8.6 (br, 1H, --CO₂ H), 6.02 [br, 1H, (CH₃)₂ --C═CH),3.8 (m, 3H, C--CH₂ --O--C, O--C--CH--O), 2.06 (d, J=1 Hz, 3H, CH₃--C═CH--).

EXAMPLE 2022S,3R,6S-6-Carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 201 but substituting an equivalentamount of2S,3R,6E-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-olfor2S,3R,6E-6-(2-hydroxyethylidene)-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-oxepan-3-ol,there is obtained2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

IR (neat) μ: 2.78-4.00 (br), 5.78 (s), 5.86 (s); NMR_(TMS)^(CDCl).sbsp.3 δ: 8.8 (br, 1H, CO₂ H), 5.3 [br, 1H, (CH₃)₂ --C═CH), 3.8(m, 3H, C--CH₂ --OC, O--C--CH--O), 3.1 (bd, J=7 Hz, 2H, C═C--CH₂ --CO),1.75 (bs, 3H, CH₃ --C═C), 1.62 (bs, 3H, CH₃ --C═C).

EXAMPLE 2032S,3R,6S-6-Carboxy-2-methyl-2-(5-hydroxy-4,8-dimethyl-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 18 but substituting an equivalentamount of2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6E-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S,3R-6S-6-carboxy-2-methyl-2-(5-hydroxy-4,8-dimethyl-7-nonenyl)-3,6-oxidooxepane.

IR (neat) μ: 2.78-4.00 (br), 5.78 (s); NMR_(TMS) ^(CDCl).sbsp.3 δ: 5.3[br, 1H, (CH₃)₂ --C═CH ), 3.8 (m, 4H, C--CH₂ --O--C and --O--C--CH--O,--HOCH--), 1.75 (bs, 3H, CH₃ --C═C), 1.62 (bs, 3H, CH₃ --C═C).

EXAMPLE 2042S,3R,6R-2-Methyl-6-chloroformylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 65 but substituting an equivalentamount of2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S,3R,6R-2-methyl-6-chloroformylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 204 by substituting an equivalent amount of the appropriatecarboxylic acid for2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR405##

EXAMPLE 2052S,3R,6R-6-(2-Carboxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

A solution of2S,3R,6R-2-methyl-6-chloroformylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(400 mg.) in ether (30 ml.) is added dropwise to an ethereal solution ofdiazomethane (1.1 mmole) at 0° under argon. After keeping the reactionmixture overnight at room temperature, the ether is removed underreduced pressure. The residue is redissolved in dioxane (20 ml.) andthen added slowly to a mixture of silver oxide (127 mg.) and an aqueoussolution of sodium thiosulfate. The mixture is stirred for 3 hrs. atroom temperature while an additional quantity of silver oxide is addedin portions and the temperature is kept at 50° for 1 hr. The solution iscooled and filtered and the residue washed with a 10% sodium hydroxidesolution (3×20 ml.). The aqueous layer is acidified with 10%hydrochloric acid solution at 0° C. to pH 2˜3. The mixture is extractedwith ethyl acetate (3×15 ml.). The organic phase is dried and evaporatedin vacuo to give2S,3R,6R-6-(2-carboxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 205 by substituting an equivalent amount of the appropriatestarting material for2S,3R,6R-2-methyl-6-chloroformylmethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR406##

EXAMPLE 2062S,3R,6S-6-Carbmethoxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 60 but substituting an equivalentamount of2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,there is obtained2S,3R,6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 206 by substituting an equivalent amount of the appropriatecarboxylic acid for2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR407##

EXAMPLE 2072S,3R,6S-6-Carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,sodium salt

Following the procedure of Example 64 but substituting an equivalentamount of2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,there is obtained 2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,sodium salt.

The following compounds are prepared according to the procedure ofExample 207 by substituting an equivalent amount of the appropriatecarboxylic acid for2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-##STR408##

EXAMPLE 2082S,3R,6S-6-Chloroformyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 65 but substituting an equivalentamount of2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-3-acetoxy-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5oxo-7-nonenyl)-oxepane,there is obtained2S,3R,6S-6-chloroformyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

EXAMPLE 2092S,3R,6S-6-Carbamoyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 66 but substituting an equivalentamount of2S,3R,6S-6-chloroformyl-2-methyl-2-(4,8-dimethyl-5-oxo-7nonenyl)-3,6-oxidooxepanefor2S,3R-3-acetoxy-2-methyl-6-chloroformylmethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepane,there is obtained2S,3R,6S-6-carbamoyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 209 by substituting an equivalent amont of the appropriate acidchloride for2S,3R,6S-6-chloroformyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR409##

EXAMPLE 2102S,3R,6S-6-Carbamoyl-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 18 but substituting an equivalentamount of2S,3R,6S-6-carbamoyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S,3R,6S-6-carbamoyl-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 210 by substituting an equivalent amount of the appropriateketo-amide for2S,3R,6S-6-carbamoyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR410##

EXAMPLE 2112S,3R,6S-6-Carbmethoxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 18 but substituting an equivalentamount of2S,3R,6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R-6E-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S,3R,6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 211 by substituting an equivalent amount of the appropriateketo-ester for2S,3R,6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR411##

EXAMPLE 2122S,3R,6S-6-Carboxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane,sodium salt

Following the procedure of Example 64 but substituting an equivalentamont of2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepanefor2S-2-methyl-6-carboxymethylene-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,there is obtained 2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane, sodiumsalt.

The following compounds are prepared according to the procedure ofExample 212 by substituting an equivalent amount of the appropriatecarboxylic acid for2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.##STR412##

EXAMPLE 2132S,3R,6R-2-Methyl-6-hydroxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

To a stirred solution of lithium aluminum hydride (38 mg.) intetrahydrofuran (10 ml.) is slowly added, under nitrogen, a solution of2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(340 mg.) in tetrahydrofuran (10 ml.) and the mixture heated to refluxfor 1 hour. The cooled mixture is treated with water (˜5 ml.) followedby dilute aqueous hydrochloric acid (10 ml.) and then extracted withether. Removal of the ether in vacuo affords2S,3R,6R-2-methyl-6-hydroxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 213 by substituting an equivalent amount of the appropriatecarboxylic acid for2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.##STR413##

EXAMPLE 2142S,3R,6S-2-Methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

To a stirred and cooled (-60° C.) solution of2S,3R-6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(354 mg.) in toluene (10 ml.) is added, under nitrogen, a solution ofdiisobutylaluminum hydride in hexane (1.4M., 1.85 ml.). The mixture isallowed to warm to room temperature, stirred for an additional 2 hrs.and then treated with a saturated aqueous solution of ammonium chloride(˜5 ml.). The organic layer is separated, washed, dried and evaporatedin vacuo to afford2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 214 by substituting an equivalent amount of the appropriateester for2S,3R,6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxido-oxepane.##STR414##

EXAMPLE 2152S,3R,6S-2-Methyl-6-oxomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 4 but substituting and equivalentamount of2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepanefor2S,3R-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 215 by substituting an equivalent amount of the appropriatehydroxy aldehyde for2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.##STR415##

EXAMPLE 2162S,3R,6R-2-Methyl-6-hydroxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 106 but substituting an equivalentamount of2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane,there is obtained2S,3R,6R-2-methyl-6-hydroxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 216 by substituting an equivalent amount of the appropriateketo-aldehyde for2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR416##

EXAMPLE 2172S,3R,6R-2-Methyl-6-hydroxyiminomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 76 but substituting an equivalentamount of2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepanefor2S-3,3-dimethoxy-6-(2-oxoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,there is obtained2S,3R,6R-2-methyl-6-hydroxyiminomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 217 by substituting an equivalent amount of the appropriatealdehyde for2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.##STR417##

EXAMPLE 2182S,3R,6R-2-Methyl-6-hydroxyiminomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 217 but substituting an equivalentamount of2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepaneand employing 1 mole equivalent of hydroxylamine hydrochloride, there isobtained2S,3R,6R-2-methyl-6-hydroxyiminomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 218 by substituting an equivalent amount of the appropriateketo-aldehyde for2S,3R,6S-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR418##

EXAMPLE 2192S,3R,6R-6-Cyano-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 77 but substituting an equivalentamount of2S,3R,6R-2-methyl-6-hydroxyiminomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S-3,3-dimethoxy-6-(2-hydroxyiminoethylidene)-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-oxepane,there is obtained2S,3R,6R-6-cyano-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 219 by substituting an equivalent amount of the appropriateoxime for2S,3R,6R-2-methyl-6-hydroxyiminomethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.##STR419##

EXAMPLE 2202S,3R,6R-6-Cyano-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 18 but substituting an equivalentamount of2S,3R,6R-6-cyano-2-methyl-2-(4,8-dimethyl-5oxo-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6E-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-ol,there is obtained2S,3R,6R-6-cyano-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.

The following compounds are prepared according to the procedure ofExample 220 by substituting an equivalent amount of the appropriateketo-nitrile for 2S,3R,6R-6-cyano-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane. ##STR420##

EXAMPLE 2212S,3R,6R-6-Carbmethoxyethyl-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-3,6-oxidooxepane

Following the procedure of Example 74 but substituting an equivalentamount of2S,3R,6R-6-carbmethoxyethyl-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepanefor2S-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-oxepan-3-one,there is obtained2S,3R,6R-6-carbmethoxyethyl-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-3,6-oxidooxepane.

EXAMPLE 2222S,3R,6R-2-Methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-3,6-oxido-6-(2-carbmethoxypropyl)-oxepane

A solution of n-butyl lithium in hexane (2.4M., 0.417 ml.) is added to asolution of diisopropylamine (95 mg.) in anhydrous tetrahydrofuran (2ml.) at -78° C. under nitrogen. After stirring for 15 minutes, asolution of2S,3R,6R-6-carbmethoxyethyl-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-3,6-oxidooxepane(426 mg.) in anhydrous tetrahydrofuran (1 ml.) is added. After stirringfor 0.5 hr., a solution of methyl iodide (0.156 mg.) in anhydroustetrahydrofuran (1 ml.) is added. The mixture is allowed to attain roomtemperature, quenched with water and extracted with ether. The etherextract is washed, dried and evaporated to dryness to afford2S,3R,6R-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-3,6-oxido-6-(2-carbmethoxypropyl)-oxepane.

When ethyl, propyl, butyl or allyl iodide is employed in place of methyliodide, the corresponding carbalkoxyalkyl derivative is obtained.

EXAMPLE 2232S,3R,6R-2-Methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxido-6-(2-carboxypropyl)-oxepane

A mixture of2S,3R,6R-2-methyl-2-(5,5-dimethoxy-4,8-dimethyl-7-nonenyl)-3,6-oxido-6-(2-carbmethoxypropyl)-oxepane(440 mg.), methanol (6 ml.) and saturated aqueous potassium carbonatesolution (2 ml.) is stirred at 0° for 2 hrs. under argon. The solvent isremoved in vacuo and the residue is treated with chloroform (18 ml.) and20% aqueous trifluoroacetic acid (4 ml.). The resulting mixture isstirred at room temperature for 3 hrs. under argon. The reaction mixtureis treated with ethyl acetate (20 ml.) and water (10 ml.). The organiclayer is separated and dried (Na₂ SO₄). The solvent is removed to afford2S,3R,6R-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxido-6-(2-carboxypropyl)-oxepane.

EXAMPLE 2242S-3-Acetoxy-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane

A mixture of2S-3-hydroxy-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane(368 mg), ether (10 ml), acetic anhydride (0.2 ml) and pyridine (1 ml)is stirred for 16 hours at room temperature under nitrogen. Theresulting mixture is treated with ether (50 ml) and water (10 ml). Theorganic layer is washed with aqueous cupric sulfate solution (2×50 ml)and dried. The solvent is removed in vacuo to give2S-3-acetoxy-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.

EXAMPLE 2252S,3R,6R-2-Methyl-6-carboxymethyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-3,6-oxidooxepane

To a stirred suspension of pre-reduced platinum oxide (0.50 g) in water(50 ml) is added sodium bicarbonate (0.95 g) and2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepan-3-ol(0.40 g) in acetone (20 ml) and water (30 ml). The mixture is stirred atroom temperature under an oxygen atmosphere for 22 hours. The platinummetal is removed by filtration through a pad of celite. The filtrate isevaporated to dryness in vacuo. The residue is dissolved in water (200ml) and extracted with ethyl acetate (2×200 ml). The aqueous layer isacidified to pH 3 with dilute aqueous hydrochloric acid and quicklyextracted with ethyl acetate (2×200 ml). The organic layer is washedwith brine, dried (Na₂ SO₄) and evaporated to give an oily residue whichis purified on preparative tlc plates (1:9, isopropanol:chloroform) toafford2S,3R,6R-2-methyl-6-carboxymethyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-3,6-oxidooxepane (0.236 g):

IR (neat) μ: 2.90 (OH), 5.80 (C═O); NMR (CDCl₃ -TMS) δ: 1.63 and 1.73[both s, 3H each, (CHHD 3)₂ --C═CH--], 2.60 (s, 2H, CHHD 2--COOH), 3.36and 3.73 (each d, J=11 Hz, each 1H, 7--CHHD 2).

EXAMPLE 2262S,3R,6R-2-Methyl-6-carboxymethyl-2-[5-oxo-4,7,8-trimethyl-6E-nonenyl]-3,6-oxidooxepane

Following the procedure of Example 225 but substituting an equivalentamount of2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-[5-oxo-4,7,8-trimethyl-6E-nonenyl]-oxepan-3-olfor2S,3R-6-(2-hydroxyethylidene)-2-methyl-2-(5-hydroxy-4,5,8-trimethyl-7-nonenyl)-oxepan-3-ol),2S,3R,6R-2-methyl-6-carboxymethyl-2-[5-oxo-4,7,8-trimethyl-6E-nonenyl]-3,6-oxidooxepane(64% yield) is obtained.

IR (neat) μ: 5.81 (COOH), 5.90 (C═O), 6.15 (C═C); NMR (CDCl₃ -TMS) δ:1.30 (s, 3H, 2--CHHD 3), 2.07 (s, 3H, CHHD 3C═C), 2.60 (s, 2H, CHHD2--COOH), 3.35 and 3.75 (each d, J=12 Hz, each 1H, 7--CH₂).

EXAMPLE 2272S,3R,6R-6-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxynonyl)-3,6-oxidooxepane

A solution of2S,3R,6R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane(234 mg) in ethyl acetate (150 ml) is hydrogenated in the presence of 5%palladium-carbon (200 mg) at atmospheric pressure for 2 hours. Themixture is filtered through a pad of celite and the solvent evaporatedin vacuo to give an oily residue. This crude product is purified onpreparative tlc plates to afford2S,3R,6R-6-(2-hydroxyethyl-2-methyl-2-(4,8-dimethyl-5-hydroxynonyl)-3,6-oxidooxepane(0.105 g), m.p.=88°-90°:

IR (neat) μ: 2.90 (OH); NMR (CDCl₃ -TMS) δ: 0.88 [d, J=6 Hz, 9H, (CHHD3)₂ --CH and CHHD 3--CH], 1.30 (s, 3H, CHHD 3--C--), 3.19 and 3.78 (eachd, J=11 Hz, each 1H, CHHD 2--O).

EXAMPLE 2282S,3R,6R-6-(2-Oxoethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxynonyl)-3,6-oxidooxepane

Following the procedure of Example 227 but substituting an equivalentamount of2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane,2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxynonyl)-3,6-oxidooxepane(54% yield) is obtained.

IR (neat) μ: 2.86 (OH), 3.64 (CHO) and 5.80 (C═O); NMR (CDCl₃ -TMS) δ:0.90 [d, J=6 Hz, 9H, (CHHD 3)₂ --CH and CHHD 3--CH], 1.33 (s, 3H, CHHD3--C--), 2.60 (d, J=2 Hz, 2H, CHHD 2--CHO), 3.29 and 3.74 (each d, J=11Hz, each 1H, O--CHHD 2--), 9.78 (t, J=2 Hz, 1E, CH).

EXAMPLE 2292S,3R,6R-2-Methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxynonyl)-3,6-oxidooxepane

Following the procedure of Example 227 but substituting an equivalentamount of2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepanefor2S,3R,6R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane,2S,3R,6R-2-methyl-6-carboxymethyl-2-(4,8-dimethyl-5-hydroxynonyl)-3,6-oxidooxepane(35% yield) is obtained, mp 93°-94°:

IR (neat) μ: 2.90 (OH), 5.80 (COOH); NMR (CDCl₃ - TMS) δ: 0.88 [d, J=6Hz, 9H, (CHHD 3)₂ CH and CHHD 3--CH], 1.33 (s, 3H, CHHD 3--C--), 2.60(s, 2H, CHHD 2--COOH), 3.39 and 3.78 (both d, J=11 Hz, each 1H, O--CHHD2--).

EXAMPLE 2302S,3R,6R-6-(2-Hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane

A suspension of sodium borohydride (125 mg) in benzene (25 ml) istreated with acetic acid (165 mg) and refluxed for 1 hour undernitrogen. To this reagent is added2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxido-oxepane(286 mg) in benzene (10 ml). The resulting mixture is refluxed for 5hours under nitrogen. The resulting mixture is treated with water (30ml) and extracted with methylene chloride (2×150 ml). The organic layeris dried and the solvent removed in vacuo to give a yellow oil which ispurified on preparative tlc plates (2:5, ethyl acetate:chloroform) togive2S,3R,6R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxononyl)-3,6-oxidooxepane(0.197 g):

IR (neat) μ: 2.86 (OH) and 5.85 (C═O); NMR (CDCl₃ -TMS) δ: 0.88 [d, J=6Hz, 6H, (CHHD 3)₂ --CH], 1.06 (d, J=7 Hz, 3H, CHHD 3--CH), 1.30 (s, 3H,CHHD 3--C), 3.19 and 3.78 (each d, J=11 Hz, each 1H, O--CHHD 2--).

EXAMPLE 2312S,3R-3-Acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

A solution of2S,3R-3-acetoxy-6-(2-acetoxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(940 mg) in methanol (36 ml) is treated at 0° with potassium carbonate(489 mg) in water (25 ml) for 5 hours under nitrogen. The mixture istreated with water (500 ml) and extracted with ether (2×500 ml). Theorganic layer is dried and the solvent removed in vacuo to give an oilyresidue which is purified on preparative tlc plates to give2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(0.553 g).

EXAMPLE 2322S,3R-3-Acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

A mixture of2S,3R-3-acetoxy-6-(2-hydroxyethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(553 mg), manganese dioxide (1 g) and methylene chloride (100 ml) isstirred for 89 hours under nitrogen. The manganese dioxide is filtered,washed with methylene chloride and the solvent removed in vacuo to givean oil which is purified on preparative tlc plates (3:2, ethylacetate:hexane) to give2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(0.296 g).

EXAMPLE 2332S,3R-3-Acetoxy-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane

A mixture of2S,3R-3-acetoxy-6-(2-oxoethylidene)-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(396 mg), sodium cyanide (229.3 mg), acetic acid (96 mg), manganesedioxide (1.81 g) and methanol (100 ml) is stirred at room temperaturefor 19 hours under nitrogen. The maganese dioxide is filtered, washedwith methylene chloride and the solvent removed in vacuo to give an oilyresidue. This crude product is diluted with water (400 ml) and extractedwith ether (2×500 ml). The organic layer is dried and the solventremoved in vacuo to give an oil which is purified on preparative tlcplates (3:2, ethyl acetate:hexane) to give2S,3R-3-acetoxy-2-methyl-6-carbmethoxymethylene-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-oxepane(0.145 g):

IR (neat) μ: 2.92 (OH), 5.78 (COOCH₃) and 5.80 (OCOCH₃); NMR (CDCl₃-TMS) δ: 0.90 (d, J=6 Hz, 3H, CHHD 3--CH), 1.15 (s, 3H, CHHD 3--C--),1.63 and 1.73 [both s, 3H each (CHHD 3)₂ --C═C], 2.03 (s, 3H, OCOCHHD3), 3.68 (s, 3H, COOCHHD 3), 5.65 (bs, 1H, ═CHOOCH₃).

PREPARATION OF STARTING MATERIAL (CRUDE EXTRACT)

Ten kg. of dried or fresh leaves from the zoapatle plant and 30 gallonsof water are added to a 100 gallon steam-jacketed stainless steel tank.The mixture is heated at 98°-100° C. for 2.5 hours with periodicstirring. The hot mixture is filtered through gauze to afford a cleardark tea, about 25 gallons in volume. The solid residue in the tank iswashed with 4 gallons of hot water, filtered, and the filtrate combinedwith the tea obtained above. The combined aqueous extracts are extractedwith 30 gallons of ethyl acetate. The mixture is stirred vigorously andallowed to settle. The top frothy layer is siphoned off to break theemulsion, and as much ethyl acetate separated as possible. Another 20gallons of ethyl acetate are added to the mixture and the above processrepeated. The combined ethyl acetate extracts are evaporated at 50° C.under vacuum. The residue is extracted with three portions of hot(75°-80°) benzene (10 liters total). The benzene extracts are evaporatedat 50° C. under vacuum and the residue is washed three times with atotal of 8 liters of refluxing hexane. The hexane-washed residue isdissolved in 2 liters of acetone, 10 g. of Nuchar is added, and themixture is stirred 1 hour at room temperature. The charcoal is removedby filtration, and the filtrate evaporated by distillation at 30° C.under vacuum to afford 69 g. of crude extract. This crude extract isused as the starting material in Examples 1 and 25.

The following general procedure is a standard procedure employed todetect uterine contractions in female animals.

PROCEDURE I

Mature female New Zealand rabbits are anesthetized with sodiumpentobarbital and ovariectomized. Following a recovery period of oneweek, the rabbits are treated with 5 μg./day s.c. of 17μ-estradiol for 6consecutive days, followed by treatment with 1.0 mg./day s.c. ofprogesterone for 7 consecutive days. The uterus and oviducts of therabbits are perfused 72 hours after the last dose of progesteroneaccording to the method of Heilman et al., (Fertil. Steril. 23:221-229)with slight modifications. The oviduct and uterus are perfused at a rateof 53 μl./min. The uterus is perfused with a tube extending 1.0 cm. intothe lumen of the uterus from the oviducal end. The uterus is ligated atthe utero-tubal junction. Another cannula is inserted 1.0 cm. into theuterus through a small incision in the vagina in order to collectperfusate. The material to be tested is administered i.v. through thejugular vein in a vehicle that contains polyethylene glycol 200,polyethylene glycol 400, ethanol and a phosphate buffer. The cannula isattached to a P23-Dc Stathan transducer which in turn is coupled to aGrass Model 5 polygraph and the uterine contractility measured.

The following general procedure is a standard procedure employed todetect interruption of pregnancy after implantation has occurred.

PROCEDURE II

Mature, Hartley strain, female guinea pigs are continuously cohabited(monogamously) with males until a vaginal plug (copulation plug) isfound in the cage. This time is considered to be day 1 of gestation.Groups of 5-6 females are given test materials intraperitoneally in avehicle comprised of an emulsion of sesame oil and water on day 22 ofgestation. The pigs are sacrificed between the 25th and 45th day ofgestation and examined for evidence of resorption or abortion.

What is claimed is:
 1. A compound selected from the group consisting of:##STR421## wherein R₁ is --XY wherein X is hydrogen or hydroxy providedthat when X is hydrogen, Y is hydrogen; methyl; hydroxy; lower alkoxy;cycloalkoxy; phenoxy; substituted phenoxy wherein the substituent isnitro, halo or lower alkyl having 1-5 carbon atoms; trialkylsilyloxy;--OCOR' wherein R' is lower alkyl, cycloalkyl, phenyl, and substitutedphenyl wherein the substituent is nitro, halo or lower alkyl having 1-5carbon atoms; a sulfate, nitrate or phosphate radical; thiol; alkylthio;phenylthio and substituted phenylthio wherein the substituent is nitro,halo or lower alkyl having 1-5 carbon atoms; halo; amino; alkylamino;dialkylamino; phenylamino and substituted phenylamino wherein thesubstituent is nitro, halo or lower alkyl having 1-5 carbon atoms; andthe quaternary ammonium and acid addition salts thereof, acylaminowherein the acyl group is derived from a lower alkanoic acid having 1-8carbon atoms or from benzoic acid or substituted benzoic acid whereinthe substituent is nitro, halo or lower alkyl having 1-5 carbon atoms;--OCONHR wherein R is hydrogen or lower alkyl; and when X is hydroxy, Yis cyano; lower alkyl; lower alkenyl; lower alkynyl; propadienyl;benzyl, substituted benzyl wherein the substituent is nitro, halo orlower alkyl having 1-5 carbon atoms; phenyl; substituted phenyl whereinthe substituent is nitro, halo or lower alkyl having 1-5 carbon atoms;and R₁ is oxo; thioxo; hydroxyimino; alkoxyimino; phenyloxyimino andsubstituted phenyloxyimino wherein the substituent is nitro, halo orlower alkyl having 1-5 carbon atoms; acyloxyimino wherein the acyl groupis derived from a lower alkanoic acid having 1-8 carbon atoms or frombenzoic acid or substituted benzoic acid wherein the substituent isnitro, halo, or lower alkyl having 1-5 carbon atoms; hydrazono;alkylhydrazono; phenylhydrazono or substituted phenylhydrazono whereinthe substituent is halo, nitro and lower alkyl having 1-5 carbon atoms;phenylsulfonylhydrazono or substituted phenylsulfonylhydrazono whereinthe substituent is halo, nitro, or lower alkyl having 1-5 carbon atoms;carbamoylhydrazono; dialkoxy; methylenyl; alkylidenyl; alkylimino; orphenylimino and substituted phenylimino wherein the substituent is halo,nitro, or lower alkyl having 1-5 carbon atoms;R₄ is hydrogen; methyl ormethylenyl; R₅ is hydrogen; hydroxy; hydroperoxy or --OCOR'" wherein R'"is lower alkyl; R₇ is hydrogen; hydroxy; lower alkoxy; or --OCOR'"wherein R'" is lower alkyl; R₈ is --COOH and the ammonium and alkalimetal and alkaline earth metal salts thereof; --CH₂ OH; --CHO; cyano;and --COOR' wherein R' is lower alkyl, cycloalkyl, phenyl andsubstituted phenyl wherein the substituent is halo, nitro or lower alkylhaving 1-5 carbon atoms; --COCl or --CONH₂.
 2. A compound of claim 1which compound is2S,3R,6S-6-carboxy-2-methyl-2-(5-oxo-4,7,8-trimethyl-6E-nonenyl)-3,6-oxidooxepane.3. A compound of claim 1 which compound is2S,3R,6S-6-carboxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.4. A compound of claim 1 which compound is2S,3R,6S-6-carboxy-2-methyl-2-(5-hydroxy-4,8-dimethyl-7-nonenyl)-3,6-oxidooxepane.5. A compound of claim 1 which compound is2S,3R,6S-6-carbmethoxy-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.6. A compound of claim 1 which compound is2S,3R,6S-6-carbamoyl-2-methyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.7. A compound of claim 1 which compound is2S,3R,6R-2-methyl-6-hydroxymethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.8. A compound of claim 1 which compound is2S,3R,6S,-2-methyl-6-oxomethyl-2-(4,8-dimethyl-5-hydroxy-7-nonenyl)-3,6-oxidooxepane.9. A compound of claim 1 which compound is2S,3R,6R-6-cyano-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane.10. A compound of claim 1 wherein a double bond is present at c.
 11. Amethod of interrupting pregnancy which comprises administering to femaleanimals a pregnancy interrupting effective amount of a compound of claim1 in a pharmaceutically acceptable carrier.
 12. A method of inducinguterine contractions which comprises administering to a female animal auterine contraction inducing effective amount of a compound of claim 1in a pharmaceutically acceptable carrier.